Methods of Lysergic Acid Synthesis-The Key Ergot Alkaloid

molecules
Review
Methods of Lysergic Acid Synthesis—The Key Ergot Alkaloid
Michał K. Jastrz˛ebski 1, * , Agnieszka A. Kaczor 1,2 and Tomasz M. Wróbel 1,3, *
1 Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling
Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki St., PL-20093 Lublin, Poland;
agnieszka.kaczor@umlub.pl
2 School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland
3 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences,
University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
* Correspondence: michal.jastrzebski6.stud@pw.edu.pl (M.K.J.); tomasz.wrobel@umlub.pl (T.M.W.);
Tel.: +48-81-448-72-73 (M.K.J.)
Abstract: Ergot is the spore form of the fungus Claviceps purpurea. Ergot alkaloids are indole
compounds that are biosynthetically derived from L-tryptophan and represent the largest group of
fungal nitrogen metabolites found in nature. The common part of ergot alkaloids is lysergic acid.
This review shows the importance of lysergic acid as a representative of ergot alkaloids. The subject
of ergot and its alkaloids is presented, with a particular focus on lysergic acid. All methods of total
lysergic acid synthesis—through Woodward, Hendrickson, and Szantay intermediates and Heck
coupling methods—are presented. The topic of biosynthesis is also discussed.
Keywords: lysergic acid; ergot alkaloids; total synthesis; biosynthesis
1. Lysergic Acid as a Component of Ergot Alkaloids

1.1. Ergot
Citation: Jastrz˛ebski, M.K.; Kaczor, Ergot is the spore form of the fungus Claviceps purpurea (Fr.) Tul. (see Section Abbrevi-
A.A.; Wróbel, T.M. Methods of
ations used in the text). It occurs in the form of elongated sclerotia, ranging in length from
Lysergic Acid Synthesis—The Key
a few millimeters to 4–6 cm. Ergot, in addition to causing diseases of cereal and grass, and,
Ergot Alkaloid. Molecules 2022, 27,
hence, lowering yields, also causes grain contamination with toxic substances, alkaloids,
7322. https://doi.org/10.3390/
which are harmful to both humans and animals, causing a number of diseases commonly
molecules27217322
referred to as “ergotism” [1].
Academic Editor: Lee J. Silverberg
1.1.1. History of Ergot [2]
Received: 7 September 2022
Accepted: 21 October 2022
The problem of the presence of ergot and its toxicity has existed since the agrarian
Published: 28 October 2022
revolution. There is historical evidence of their presence in numerous cultures, ranging
from the Assyrians (600 BC), through ancient Rome (1st century BC), to medieval Europe.
Publisher’s Note: MDPI stays neutral
Typically, ergot has been described as “harmful spots on the spikes” and “poisonous grass
with regard to jurisdictional claims in
causing miscarriage”. Hippocrates identified a plant disease in the 4th century BC, which he
published maps and institutional affil-
called melanthion—and described the inhibitory effect of ergot on postpartum bleeding [3].
iations.
Ergotic epidemics frequently occurred in medieval Europe. They were due to the
prevalence of contaminated rye used in baking bread. Rye often contained large amounts
of alkaloids that induced ergotism. The very first ergot epidemic was mentioned in Annales
Copyright: © 2022 by the authors.
Xantensen (Germany, 857). Numerous sources describe successive epidemics in France,
Licensee MDPI, Basel, Switzerland. Germany, and Scandinavia. The 16th century was particularly dramatic, when tens of
This article is an open access article thousands of people died in Europe from ergot poisoning. The last major epidemic took
distributed under the terms and place in Russia in 1926–1927 in the Ural region. Single cases of ergotamine poisoning have
conditions of the Creative Commons occurred since then [1,4].
Attribution (CC BY) license (https:// One of the first to make connection between illness and eating contaminated grain was
creativecommons.org/licenses/by/ the German physician Wendelin Thelius, in 1596. In 1670, Thuillier linked the presence of
4.0/). ergot in rye bread with epidemics by experimenting with feeding ergot to animals, which
Molecules 2022, 27, 7322. https://doi.org/10.3390/molecules27217322 https://www.mdpi.com/journal/molecules

One of the first to make connection between illness and eating contaminated grain
was the German physician Wendelin Thelius, in 1596. In 1670, Thuillier linked the pres-
ence of ergot in rye bread with epidemics by experimenting with feeding ergot to animals,
which led to their death. At the end of the 18th century, L’Abbe Tessier proposed preven-
Molecules 2022, 27, 7322 tive measures—compulsory grain cleaning and replacing contaminated grain with pota- 2 of 56
toes in the diet. It was not until 1764 that von Münchhausen stated that ergot was a fungus
[1].
led toErgot
theirwas alsoAt
death. usedthefor
endmedicinal
of the 18thpurposes.
century,ErgotL’Abbealkaloids
Tessierwere used preventive
proposed as early as
2000 BC in Greece as a hallucinatory
measures—compulsory grain cleaningagent, in Mesopotamia
and replacing as angrain
contaminated ingredient of “magic
with potatoes in
spells”,
the diet.and in Egypt
It was not untilin a1764
formulation described as a stated
that von Münchhausen hair growth remedy.
that ergot was aThe first[1].
fungus con-
firmed reports
Ergot of the
was also deliberate
used use ofpurposes.
for medicinal ergot come Ergotfrom aroundwere
alkaloids 1100used
B.C.E. from as
as early China,
2000
where it was as
BC in Greece used in obstetrics and
a hallucinatory gynecology.
agent, in MesopotamiaIn the as
16than century,
ingredient ergot was also
of “magic used
spells”,
for
andmedical
in Egyptpurposes in the West—Adam
in a formulation described asLonicer used it to
a hair growth induceThe
remedy. labor,
firstand Thalius
confirmed
reports
used of the
ergot to deliberate
stanch theuse of ergotIncome
bleeding. 1820,from
ergotaround 1100 B.C.E.into
was introduced fromthe
China,
Unitedwhere
States it
was used in obstetrics
Pharmacopoeia [1]. and gynecology. In the 16th century, ergot was also used for medical
purposes in the West—Adam
Nowadays, the presence Lonicer
of ergot used it to is
in cereal induce labor,aand
no longer ThaliusGrain
problem. usedcleaning
ergot to
stanch the bleeding.
techniques In 1820,
used in mills ergot
remove upwas introduced
to 82% the Unitedin
intocontained
of the ergot States
them.Pharmacopoeia
In addition, the[1].
Nowadays,
process of bakingthe presence
wheat breadof ergotfor
allows in the
cereal is no longer
reduction of theaconcentration
problem. Grain cleaning
of alkaloids,
techniques
even to zeroused
[4]. in mills remove up to 82% of the ergot contained in them. In addition, the
process of baking wheat bread allows for the reduction of the concentration of alkaloids,
even to
1.1.2. zero [4]. of Ergot
Properties
As described above, ergot is both toxic and therapeutic [4]. Two different forms of
1.1.2. Properties of Ergot
ergot poisoning have been described: ergotismus gangrenosus (gangrene, “St. Anthony’s
fire”)As
anddescribed
ergotismus above, ergot is (contractile
convulsivus both toxic and therapeutic
form, [4]. Two The
“St. Vitus dance”). different formscan
two forms of
ergot poisoning have been described: ergotismus gangrenosus (gangrene, “St. Anthony’s
coexist or be independent of each other. Symptoms present in gangrenous form, include
fire”) and ergotismus convulsivus (contractile form, “St. Vitus dance”). The two forms
diarrhea, sensory disturbances, slow heart rate, shortness of breath, paralysis of the res-
can coexist or be independent of each other. Symptoms present in gangrenous form,
piratory center, ischemia affecting the limbs, thrombotic changes followed by gangrene,
include diarrhea, sensory disturbances, slow heart rate, shortness of breath, paralysis of the
loss of limbs, and death. In the case of the systolic form, symptoms comprise of sensory
respiratory center, ischemia affecting the limbs, thrombotic changes followed by gangrene,
disturbances, muscle tremors, headache, abdominal pain, slow heart rate, and, at the same
loss of limbs, and death. In the case of the systolic form, symptoms comprise of sensory
time, strong nervous excitation [3,4].
disturbances, muscle tremors, headache, abdominal pain, slow heart rate, and, at the same
Ergot is also toxic to animals, causing symptoms similar to those observed in humans:
time, strong nervous excitation [3,4].
loss of milk, convulsive ergotism, and gangrene.
Ergot is also toxic to animals, causing symptoms similar to those observed in humans:
The therapeutic effects of ergot may include inhibition of prolactin, treatment of par-
loss of milk, convulsive ergotism, and gangrene.
kinsonism [5], treatment of cerebrovascular insufficiency, migraine, venous insufficiency,
The therapeutic effects of ergot may include inhibition of prolactin, treatment of
thrombosis, embolism,
parkinsonism stimulation
[5], treatment of cerebral,insufficiency,
of cerebrovascular peripheral metabolism, and stimulation
migraine, venous of
insufficiency,
the uterus [1,4].
thrombosis, embolism, stimulation of cerebral, peripheral metabolism, and stimulation of
Moreover,
the uterus [1,4]. ergot alkaloids have been used to induce abortion for hundreds of years
[3]. Moreover, ergot alkaloids have been used to induce abortion for hundreds of years [3].
1.2. Ergot Alkaloids

1.2.1. Types of Ergot Alkaloids
Ergot alkaloids are based on the ergoline
ergoline ring
ring system
system (Figure
(Figure 1).
1).
Figure 1. Structure of ergoline.
Ergoline derivatives
derivativeshave
havetwo
twoasymmetric
asymmetric centers, either
centers, at the
either C-5C-5
at the andand
C-10C-10
positions
posi-
or at the C-5 and C-8 positions. The stereochemistry and configuration of all atoms
tions or at the C-5 and C-8 positions. The stereochemistry and configuration of all atoms in the
structures are accurately described in the literature, in particular the relative positions of
the hydrogen [6,7].
Ergot alkaloids are indole compounds that are biosynthetically derived from L-tryptophan
and represents the largest group of fungal nitrogen metabolites found in nature. Ergot
contains 0.15% to 0.5% of alkaloids, which can be separated by analytical methods into
individual ones, with more than 80 individual ergot alkaloids [2].
in the structures are accurately described in the literature, in particular the relative posi-
tions of the hydrogen [6,7].
Ergot alkaloids are indole compounds that are biosynthetically derived from L-tryp-
Molecules 2022, 27, 7322 3 of 56
tophan and represents the largest group of fungal nitrogen metabolites found in nature.
Ergot contains 0.15% to 0.5% of alkaloids, which can be separated by analytical methods
into individual ones, with more than 80 individual ergot alkaloids [2].
There
There areare five
fivemain
maingroups
groups depending
depending on R
on the the R substituent
substituent in thein
C-8the C-8 position
position (Figure
(Figure
2) [8,9]. 2) [8,9].
Figure 2. Structural
Figure Structuralformulas
formulasofofthe
the5 main groups
5 main groupsof ergot alkaloids:
of ergot (a) clavine
alkaloids: alkaloids
(a) clavine and (b)
alkaloids and
6,7-secoergolenes
(b) 6,7-secoergolenes (alkaloids with
(alkaloids an an
with open D ring),
open (c) (c)
D ring), lysergic acid
lysergic derivatives,
acid derivatives,(d) (d)
peptide alka-
peptide alka-
loids, and
loids, and (e)
(e) lactam
lactam ergot
ergot alkaloids.
alkaloids.
Ergot alkaloids
Ergot alkaloidscan
canalso
alsobe beclassified
classifiedaccording
accordingtoto their
their molecular
molecular weight.
weight. LowLow mo-
molec-
lecular
ular weight
weight ergot
ergot alkaloids
alkaloids are are amides
amides of lysergic
of lysergic (or isolysergic)
(or isolysergic) acidacid
andand
aminoamino alco-
alcohols.
hols. Ergometrine
Ergometrine (ergobasine,
(ergobasine, ergonovine,
ergonovine, ergoklinine,
ergoklinine, ergostetrine,
ergostetrine, and ergotocine)
and ergotocine) is an amide is
an2-aminopropanol
of amide of 2-aminopropanol
and lysergic and
acid,lysergic acid, and ergometrinine
and ergometrinine (ergobasinine and(ergobasinine and
isoergometrine)
isoergometrine)
is is an amide
an amide of isolysergic of isolysergic
acid. High molecularacid. High molecular
weight weight ergot
ergot alkaloids alkaloids are
are oligopeptides
consisting of a ring of three amino acids (always with proline), linked to lysergiclinked
oligopeptides consisting of a ring of three amino acids (always with proline), to
acid by
alysergic
peptideacid
bond.by These
a peptide bond. Thesesuch
are compounds are compounds suchergotin,
as: ergotamine, as: ergotamine,
ergosine,ergotin, er-
ergotoxin,
gosine, ergotoxin,
ergocryptine, ergocryptine,
ergocristine, ergocristine,
ergoclavine, ergoclavine,[1].
and chanoclavine and chanoclavine [1].
1.2.2.
1.2.2. Biochemical
Biochemical and and Pharmacological
Pharmacological Properties
Properties
Ergot
Ergot alkaloids—derivatives of D-lysergicacid—act
alkaloids—derivatives of D-lysergic acid—actbybyantagonistic oror
antagonistic agonistic affin-
agonistic af-
ity to α
finity to adrenergic
α adrenergic receptors
receptorsasaswell
wellasastotoserotonin
serotoninreceptors
receptorsand
anddopamine
dopamine receptors
receptors
(D
(D11–D
–D55)) [10].
[10]. This
This isis due
duetotothe
thestructural
structuralsimilarity to to
similarity endogenous
endogenousamines—noradrenaline,
amines—noradrena-
dopamine [11], and serotonin [12] (Figure
line, dopamine [11], and serotonin [12] (Figure 3). 3).
In medicine, ergotamine, dihydroergotamine, dihydroergotoxin, and dihydroergocristine,
as well as their mixtures, are used [10].
These compounds are applied in medicine as sedatives and painkillers. They are also
used as antispasmodics (in migraine attacks and in gynecology, in particular ergotamine);
as drugs in orthostatic hypotension, in the treatment of intellectual disorders, and after
strokes (for example, dihydroergotoxins) [10].
Molecules 2022,
Molecules 2022, 27,
27, 7322
x FOR PEER REVIEW 44 of 56
of 56
Figure 3. Structural formulas of endogenous amines and lysergic acid.
In medicine, ergotamine, dihydroergotamine, dihydroergotoxin, and dihydroer-

gocristine, as well as their mixtures, are used [10].
These compounds are applied in medicine as sedatives and painkillers. They are also
used as antispasmodics (in migraine attacks and in gynecology, in particular ergotamine);
as drugs
Figure in orthostatic
3. Structural
Structural formulashypotension,
of endogenous
endogenous in the treatment
amines of intellectual
and lysergic
lysergic acid. disorders, and after
Figure 3. formulas of amines and acid.
strokes (for example, dihydroergotoxins) [10].
Lysergic
Lysergic
In medicine,acid diethylamide
acid diethylamide (LSD) (Figure
(LSD)
ergotamine, dihydroergotamine,(Figure 4) 4) is
is aadihydroergotoxin,
semisynthetic hallucinogenic
semisynthetic hallucinogenic
and dihydroer-com-
pound.
pound. It
It isis one
one of
of the
the most
most active
active psychedelic
psychedelic
gocristine, as well as their mixtures, are used [10]. substances
substances with
with hallucinogenic
hallucinogenic effects—
effects—the
the mild
mild effects
These effects appear
appear
compounds at aat a applied
dose
are dose of µg.
of 25 25 µ LSD
g. LSD
in medicine isasan
is an agonist
agonist
sedatives ofof thepainkillers.
the
and 5-HT
5-HT receptor
2A2Areceptor located
They located
are also
on
on the
the inhibitory
inhibitory interneurons
interneurons of
of the
the brain.
brain. However,
However, the
the action
action
used as antispasmodics (in migraine attacks and in gynecology, in particular ergotamine); of
of LSD
LSD is
is not
not limited
limited to
to
that
that
as of the
of
drugs theinserotonin
serotonin
orthostaticreceptors.
receptors. Although
Although
hypotension, LSD
LSD
in the and the
and
treatmentthe other
other psychoactive
psychoactive
of intellectual derivatives
derivatives
disorders, exert
and exert
after
their
their effects
effects through
through activation
activation of
of
strokes (for example, dihydroergotoxins) [10]. 5-HT
5-HT 2A receptors,
2A receptors, they
they can
can have
have aa significant
significant behavioral
behavioral
component
component
Lysergic mediated
mediated by
byactivation
activation
acid diethylamide of
(LSD)of5-HT
5-HT 1A receptors
(Figure
1A receptors [13,14].
[13,14]. Moreover,
Moreover,
4) is a semisynthetic LSD
LSDalso
alsohas
hallucinogenic has an
an
com-
effect
effect on
on the
the dopamine
dopamine
pound. It is one of the most DD 11 and
and DD receptors [15].
2 psychedelic substances with hallucinogenic effects—
2
active
the mild effects appear at a dose of 25 µ g. LSD is an agonist of the 5-HT2A receptor located
on the inhibitory interneurons of the brain. However, the action of LSD is not limited to
that of the serotonin receptors. Although LSD and the other psychoactive derivatives exert
their effects through activation of 5-HT2A receptors, they can have a significant behavioral
component mediated by activation of 5-HT1A receptors [13,14]. Moreover, LSD also has an
effect on the dopamine D1 and D2 receptors [15].
Figure4.
Figure 4. Ergot
Ergot alkaloid
alkaloidderivatives.
derivatives.
Due to a short-term reduction in serotonin levels, after the LSD interaction with cells
subsides, its production in the cells increases abruptly, which may cause disintegration
of cortical–cortical neuronal activity—and, consequently, induce increased perception of
sensory stimuli and cognitive impairment [16]. Interestingly, LSD is not addictive, and
despite the fact that it is not currently used in medicine, there are ongoing studies on its
Figure 4. Ergot alkaloid derivatives.
use in psychiatry—e.g., in the fight against alcoholism [17,18].
Due to a short-term reduction in serotonin levels, after the LSD interaction with cells
subsides, its production in the cells increases abruptly, which may cause disintegration of
cortical–cortical neuronal activity—and, consequently, induce increased perception of
Molecules 2022, 27, 7322 sensory stimuli and cognitive impairment [16]. Interestingly, LSD is not addictive,5 of and
56
despite the fact that it is not currently used in medicine, there are ongoing studies on its
use in psychiatry—e.g., in the fight against alcoholism [17,18].
Ergotalkaloids
Ergot alkaloidscause
causeeffects
effectssuch
suchasas vasoconstriction,
vasoconstriction, uterine
uterine contraction,
contraction, andand ergot-
ergotism
ism of varying intensity (Table 1)
of varying intensity (Table 1) [19]. [19].
Table 1. Activity profile of ergot alkaloids—lysergic acid derivatives.

Table 1. Activity profile of ergot alkaloids—lysergic acid derivatives.
Lysergic Acid Uterotonic
Lysergic Acid Ergotism
Ergotism
Uterotonic Vasoconstriction
Vasoconstriction
Derivatives
Derivatives Contraction
Contraction
Ergotamine Very strong effect Strong effect Very strong effect
Ergotamine Very strong effect Strong effect Very strong effect
Dihydroergotamine
Dihydroergotamine Moderate
Moderate effect effect Moderate effect
Moderate effect Strong effect
Strong effect
Lysergic acid
Lysergic acid amides 1
amides Moderate
1 Moderate effect
effect Very strong effect
Very strong effect Moderate effect
Moderate effect
LSDLSD Strong effect
Strong effect Strong effect
Strong effect Moderate effect
Moderate effect
11 ergometrine
and methylergometrine.
ergometrine and methylergometrine.
1.2.3.
1.2.3. Other
Other Application
Application [20]
[20]
According thelatest
According to the latestreports,
reports,a semisynthetic
a semisynthetic lysergic
lysergic acidacid derivative
derivative contain-
containing a
ing a urethane
urethane bond atbond
the at
C-8the C-8 substituent—metergoline
substituent—metergoline (Figure(Figure 5), interesting
5), has an has an interesting
antibac-
antibacterial application.
terial application.
Figure 5.
Figure 5. Metergoline.
Metergoline.
This
This compound is is authorized
authorizedunder underthe thetrade
trade names
names Contralac
Contralac andand Liserdol
Liserdol as aashy-
a
hyperprolactinemia
perprolactinemia drug drug[21].
[21].Previous
Previousstudies
studieshave
haveindicated
indicateditsits agonistic
agonistic activity towards
towards
the
the 55 HT1A,
HT1A, 5-HT1D,
5-HT1D, and and 5-HT1B
5-HT1B receptors,
receptors, as as well
well as
as antagonistic
antagonistic activity
activity towards
towards thethe
5-HT
5-HT2A 2A, 5-HT2B 2B, ,5-HT
5-HT2C2C, and
, and5-HT
5-HT 77 receptors[22,23].
receptors [22,23].
The
The latest
latest data,
data, published
published in 2022 by Brown and Magolan [20], indicate that meter-
goline
goline is an inhibitor of the
is an inhibitor of the intracellular
intracellular Gram-negative pathogen Salmonella
Gram-negative pathogen typhimurium.
Salmonella typhimurium.
The
The biomechanism of action assumes a change in the permeability of the outer membrane
biomechanism of action assumes a change in the permeability of the outer membrane
of
of SPR741,
SPR741, which
which allows
allows forfor an
an increase
increase inin the
the potential
potential ofof biological
biological activity
activity against
against the
the
MRSA strains WT
MRSAstrains, , WT E. E.
coli, Acinetobacter
coli, Acinetobacterbaumannii,
baumannii, Burkholderia
andand cenocepacia.
Burkholderia The authors
cenocepacia. The au-
suggest that the
thors suggest thatergot scaffold
the ergot (especially
scaffold the amide
(especially derivatives
the amide of lysergic
derivatives acid,
of lysergic such
acid, as
such
metergoline) may be the basis for the production of new efficient
as metergoline) may be the basis for the production of new efficient antibiotics. antibiotics.
1.3. Lysergic Acid

1.3. Lysergic Acid
Lysergic acid (Figure 6) is a chemical compound based on the structure of ergoline—a
Molecules 2022, 27, x FOR PEER REVIEW Lysergic acid (Figure 6) is a chemical compound based on the structure of ergoline—
6 of in
56
four-ring system—which has a COOH acid group in the C-8 position and a methylamine
a four-ring system—which has a COOH acid group in the C-8 position and a methylamine
the 6-position in the D ring.
in the 6-position in the D ring.
Figure6.
Figure 6. d-Lysergic
d-Lysergicacid.
acid.
Lysergic acid is a very important chemical compound obtained on a large scale. This
is because it is a key precursor for the preparation of more complex ergot alkaloids, espe-
cially lysergic acid amides.
History of Lysergic Acid [24]

The isolation and analysis of ergot alkaloids began in 1906, when ergotoxine (a mix-
Molecules 2022, 27, 7322 6 of 56
Figure 6. d-Lysergic acid.
Lysergicacid
Lysergic acidisisaavery
veryimportant
importantchemical
chemicalcompound
compound obtained
obtained onon a large
a large scale.
scale. This
This is
is because it is a key precursor for the preparation of more complex ergot alkaloids, espe-
because it is a key precursor for the preparation of more complex ergot alkaloids, especially
cially lysergic
lysergic acid amides.
acid amides.
History of
History of Lysergic
LysergicAcidAcid[24][24]
The isolation
The isolationandandanalysis
analysisofofergot
ergot alkaloids
alkaloids began
began in in 1906,
1906, when
when ergotoxine
ergotoxine (a mix-
(a mixture
of three proline-based alkaloids, ergocristine, ergocriptine, and ergocornine) was iso-
ture of three proline-based alkaloids, ergocristine, ergocriptine, and ergocornine) was
lated from
lated from ergot
ergot [25],
[25], and
and its
its adrenolytic activity was discovered [26]. Twelve years later,
Stoll isolated
Stoll isolated ergotamine—the
ergotamine—the first first chemically
chemically purepure ergot
ergot alkaloid,
alkaloid, with
with major
major medical
medical
uses [27].
uses [27]. From
From that
that moment,
moment, the the research
research efforts
efforts intensified.
intensified. Since 1934, comprehensive
comprehensive
studies of
studies of ergot alkaloids have have been
beencarried
carriedoutoutbybyway
wayofofcollaboration
collaboration between
between teams
teamsin
in
thethe
USA, USA, England,
England, andand Switzerland,
Switzerland, withwith pharmaceutical
pharmaceutical companies
companies investigating
investigating the
the pharmacological
pharmacological andand clinical
clinical effects
effects [28].[28].
As aAs a result,
result, Jacobs
Jacobs and Craig
and Craig identified
identified the
the com-
common
mon partpart for ergot
for ergot alkaloids—lysergic
alkaloids—lysergic acidacid
[29].[29].
Lysergic
Lysergicacidacidisis aa chiral
chiral compound
compound with with two stereogenic
stereogenic centers.
centers. Subsequently,
Subsequently, itit was
was
possible
possible to to identify
identify all
all four
four stereoisomeric
stereoisomeric forms
forms in in which
which this
this acid
acid can occur: d-lysergic
can occur: d-lysergic
acid, l-lysergic
acid, acid, d-isolysergic
l-lysergic acid, d-isolysergic acid, and l-isolysergic
acid, and l-isolysergic acid; this has
has been
been described
described byby
Stoll, Hofmann, and Troxler (Figure
Stoll, Hofmann, and Troxler (Figure 7) [30]. 7) [30].
Figure 7.
Figure 7. Four
Four stereoisomeric
stereoisomeric forms
forms of
of lysergic
lysergic acid.
acid.
Finally,
Finally,inin1956,
1956, at
at the
the Lilly
Lilly Laboratory,
Laboratory, the
the Woodward
Woodwardgroupgroupwaswasthethe first
first to
to achieve
achieve
aa total synthesis of lysergic acid [31].
total synthesis of lysergic acid [31]. In the
the following years, further structures of
following years, further structures of ergot
ergot
alkaloids
alkaloidswere
wereidentified,
identified,and
and thethe
total syntheses
total of ergotoxine
syntheses components
of ergotoxine componentswere presented.
were pre-
An explanation of the proposed structures was summarized in the synthetic works
sented.
of Woodward [31] and
An explanation ofRamage [32]. By
the proposed examining
structures wasthe pentacyclic in
summarized styrene derivatives
the synthetic as
works
well as the 2,3-dihydrolysergic acid (+)-butanolamide in the lysergic acid
of Woodward [31] and Ramage [32]. By examining the pentacyclic styrene derivatives asderivatives [33], a
conclusion was made about the C-H bonds at C-3 and C-5 being cis and quasi-axial
well as the 2,3-dihydrolysergic acid (+)-butanolamide in the lysergic acid derivatives [33], [34].
Surprisingly,
a conclusion not only
was made is the
about thecarboxyl/ester
C-H bonds at C-3group
andatC-5
thebeing
C8 position
cis andstereoselectively
quasi-axial [34].
labile, but there is lability at both chiral centers, including at C5, leading to racemization
of the system. The balance between structures is easily shifting, e.g., isolysergic acid can
be converted to lysergic acid by boiling in methanol or by barium hydroxide in high
temperature. Moreover, the same effect can be seen in the natural racemic hydrazine
derivatives of lysergic acid [35].
Woodward, who was the first to perform a total synthesis of lysergic acid, proposed
a reaction mechanism explaining epimerization at both chiral centers. These postulates
were proved spectrally, experimentally, and crystallographically by Ramage two decades
labile, but there is lability at both chiral centers, including at C5, leading to racemization
of the system. The balance between structures is easily shifting, e.g., isolysergic acid can
be converted to lysergic acid by boiling in methanol or by barium hydroxide in high tem-
perature. Moreover, the same effect can be seen in the natural racemic hydrazine deriva-
tives of lysergic acid [35].
Molecules 2022, 27, 7322 7 of 56
Woodward, who was the first to perform a total synthesis of lysergic acid, proposed
a reaction mechanism explaining epimerization at both chiral centers. These postulates
were proved spectrally, experimentally, and crystallographically by Ramage two decades
later.
later. They
Theyproposed
proposedthat
thatthe
theracemization
racemizationprocess
processwas
wasvia
viaanan
achiral tricyclic
achiral intermediate
tricyclic intermedi-
(Figure 8), which
ate (Figure could
8), which be formed
could by retro
be formed Michael
by retro fragmentation
Michael [36].[36].
fragmentation
Figure 8.
Figure 8. Equilibrium
Equilibrium between
between the
the forms
forms of
of lysergic
lysergic acid,
acid, explaining
explaining the
the racemization
racemization mechanism.
mechanism.
2.
2. Methods
Methods ofof Lysergic
Lysergic Acid
Acid Synthesis
Synthesis
There
There are many methods of
are many methods of obtaining
obtaining lysergic
lysergic acid.
acid. They
They belong
belong toto two
two main
main types:
types:
using
using biotechnology
biotechnology andand synthetic.
synthetic. In
In total,
total, they
they allow
allow for
for the
the production
production of of 10–15
10–15 tons
tons of
of
acid
acid annually
annually [2].
[2].
The biotechnological method
The biotechnological methodofofobtaining
obtaininglysergic
lysergic acid
acid is based
is based on on Arthur
Arthur Stoll’s
Stoll’s pa-
patent, who in 1918 proposed a method for the efficient separation and purification
tent, who in 1918 proposed a method for the efficient separation and purification of er- of
ergotamine tartrate from fermented triticale and was put into production by
gotamine tartrate from fermented triticale and was put into production by Sandos in 1921. Sandos in
1921. Then, pure lysergic acid can be obtained after amide hydrolysis
Then, pure lysergic acid can be obtained after amide hydrolysis [37,38]. [37,38].
The second method
The second method isisproposed
proposedby bychemists,
chemists,and andconcerns
concerns thethe total
total synthesis
synthesis of
of ly-
lysergic acid, starting with Kornfeld in 1956 [31]. To this day, 22 methods of synthesis
sergic acid, starting with Kornfeld in 1956 [31]. To this day, 22 methods of synthesis of this of
this compound have been described.
compound have been described.
2.1. Woodward’s Strategy
2.1. Woodward’s Strategy
2.1.1. Woodward’s Research Group
2.1.1. Woodward’s Research Group
The first strategy for obtaining lysergic acid was proposed in 1956 by Woodward’s
team The
[31].first
The strategy for obtaining
total synthesis assumedlysergic acid wasof
the preparation proposed in 1956
the tricyclic by 5—1-benzoyl-
ketone Woodward’s
team [31]. The total synthesis assumed the preparation of the tricyclic
2,2a,3,4-tetrahydrobenzo[cd]indol-5(1H)-one, then introducing the amine by addingketone 5—1-ben-
the
zoyl-2,2a,3,4-tetrahydrobenzo[cd]indol-5(1H)-one, then introducing the amine
alkyl fragment at the C4 or C5 position and closing the D ring. The final step involved by adding
the isolation
Molecules 2022, 27, x FOR PEER REVIEW
the alkyl fragment
of the at the C4product—lysergic
racemic or C5 position andacid
closing theconfirmation
1 and D ring. The final
of itsstep involved
8 ofby
structure 56
the isolationtoofthe
comparison theauthentic
racemic product—lysergic
product (Scheme 1).acid 1 and confirmation of its structure by
comparison to the authentic product (Scheme 1).
Since this is the first work on the preparation of lysergic acid, emphasis has been
placed on presenting the line of reasoning described in this article. First, the synthesis of
the tricyclic Uhle ketone 8 was presented, and then attempts were made to introduce sub-
stituents into it at the C4 and C5 positions. The next section describes attempts to func-
tionalize the ketone by changing it into an unsaturated aldehyde. In the final section, the
synthesis leading to the tetracyclic lysergic acid is shown.
Scheme1.
Scheme 1. Retrosynthetic
Retrosyntheticanalysis
analysisleading
leadingto
tosubstrate
substratein
inthe
theWoodward
Woodwardstrategy.
strategy.
Preparation
Since of the
this is the firststarting
work on material. There is aofsubstituted
the preparation indole
lysergic acid, system has
emphasis in the ly-
been
placed on presenting
sergic acid the line
skeleton (Figure 9).ofIndoles
reasoning described in this
are commercially article.
available First, the synthesis
compounds, and their
of the tricyclic
derivatives canUhle ketone 8inwas
be obtained the presented,
laboratory and then attempts
according to many were made to
instructions inintroduce
the litera-
substituents
ture. into it at the C4 and C5 positions. The next section describes attempts to
functionalize the ketone
The selection of theby changing itindole
appropriate into an unsaturated
derivative wasaldehyde. In the however,
not so obvious, final section,
be-
the synthesis
cause the highleading to the
reactivity of tetracyclic
the hetero lysergic
ring canacid is shown.
produce undesirable byproducts based on
a more stable structure of naphthalene. The greater stability of naphthalene derivatives is
due to the higher resonance energy in relation to the indole [39].
Scheme 1. Retrosynthetic analysis leading to substrate in the Woodward strategy.
Preparation of the starting material. There is a substituted indole system in the ly-
sergic acid skeleton (Figure 9). Indoles are commercially available compounds, and their
Molecules 2022, 27, 7322 Scheme 1. Retrosynthetic
derivatives analysis
can be obtained in theleading to substrate
laboratory in the Woodward
according 8 of 56
strategy. in the litera-
to many instructions
ture.
Preparation
The selectionof
ofthe
the starting
appropriate material.
indoleThere is a substituted
derivative was not soindole system
obvious, in thebe-
however, ly-
sergic acid skeleton
causePreparation (Figure 9).
of the starting
the high reactivity Indoles are
material.
of the hetero commercially
There
ring can available
is a substituted
produce compounds,
undesirableindole system
byproducts and their
in the
based on
aderivatives
lysergic acidcan
more stable be obtained
skeleton (Figure
structure in9).the laboratory
Indoles
of naphthalene. according
are commercially
The greater toavailable
many
stability instructions
compounds,
of naphthalene in the
andlitera-
derivativestheir
is
ture.to the higher
derivatives
due can be obtained
resonance inenergy
the laboratory according
in relation to many
to the indole instructions in the literature.
[39].
The selection of the appropriate indole derivative was not so obvious, however, be-
cause the high reactivity of the hetero ring can produce undesirable byproducts based on
a more stable structure of naphthalene. The greater stability of naphthalene derivatives is
due to the higher resonance energy in relation to the indole [39].
Figure 9.
Figure 9. Indole scaffold
scaffold (red)
(red) in
in the
the lysergic
lysergic acid
acid molecule.
molecule.
The selection
The first of the
step was appropriate indole
to functionalize derivative
and reduce was not
the starting so obvious,
material however,
to the protected
because
derivative theofhigh reactivity of the hetero ring can produce undesirable
N-Benzoyl-3-(β-carboxyethyl)-dihydroindole byproducts based
7 [40]. N-Benzoyl-3-(β-carbox-
on a more
Figure stablescaffold
9. Indole
yethyl)-dihydroindole structure
wasofin
(red) naphthalene.
the lysergic
treated Themolecule.
acid
with thionyl greater stability
chloride to theofcorresponding
naphthalene derivatives
acid chlo-
is due
ride to then
and the higher resonance
converted energy
into ketone in relation
5 by to the indole
the Friedel–Crafts [39]. Ketone 5 can be easily
reaction.
The first
The
hydrolyzed first step
step
with was to
was to functionalize
functionalize
hydrochloric and
acid to theand reduce
freereduce the
base asthe starting
starting
well material to
material
as dehydrogenated to the
the protected
protected
over carbon
derivative
derivative
over ofofN-Benzoyl-3-(β-carboxyethyl)-dihydroindole
palladium N-Benzoyl-3-(β-carboxyethyl)-dihydroindole
to the known 3,4-dihydro-benzo[cd]indol-5-one 7 [40].7N-Benzoyl-3-(β-carboxyethyl)-
[40].
8,N-Benzoyl-3-(β-carbox-
known in the literature
yethyl)-dihydroindole
dihydroindole
as was treated
the Uhle’s ketone was
(Scheme treated
with [41].with
2)thionyl thionyl
chloride to chloride to the corresponding
the corresponding acid chlorideacid
and chlo-
then
ride and then
converted into converted
ketone 5 byintothe ketone 5 by thereaction.
Friedel–Crafts Friedel–Crafts
Ketone reaction. Ketone
5 can be easily 5 can be easily
hydrolyzed with
hydrochloric
hydrolyzed with acid hydrochloric
to the free base as well
acid to theasfree
dehydrogenated
base as well asover carbon over palladium
dehydrogenated to
over carbon
the known 3,4-dihydro-benzo[cd]indol-5-one 8, known in the literature as
over palladium to the known 3,4-dihydro-benzo[cd]indol-5-one 8, known in the literature the Uhle’s ketone
(Scheme 2) [41].
as the Uhle’s ketone (Scheme 2) [41].
Scheme 2. Obtaining Uhle’s ketone 8.
Very first attempts to obtain lysergic acid. Using the obtained ketone 5, attempts
were made to introduce nitrogen into the C4 position (Figure 10).
Scheme2.
Scheme 2. Obtaining
Obtaining Uhle’s
Uhle’s ketone
ketone 8.
8.
Molecules 2022, 27, x FOR PEER REVIEW 9 of 56
Very
Veryfirst
firstattempts
attemptstotoobtain
obtainlysergic acid.Using
lysergicacid. Usingthe
theobtained
obtained ketone
ketone 5,5, attempts
attempts
were
weremade
madetotointroduce
introducenitrogen
nitrogeninto
intothe
theC4
C4position
position(Figure
(Figure10).
10).
Figure 10.
Structural formulas
formulas of
of amine
amine derivatives
derivatives (9
(9 and
and 10).
10).
Attempts
Attemptswere
weremade
madetoto obtain
obtain compounds
compounds with freefree
with amine or diamine,
amine but allbut
or diamine, attempts
all at-
failed
temptsatfailed
various stages of
at various the synthesis.
stages The reaction
of the synthesis. of the of
The reaction 4-bromo derivative
the 4-bromo with
derivative
methylamine had ahad
with methylamine complicated
a complicatedcourse, leading
course, to thetonaphthalene
leading the naphthalene derivative 14. On
derivative 14. the
On
other hand, conversion of ketone 5 to O-toluenesulfonic oxime 15 allowed
the other hand, conversion of ketone 5 to O-toluenesulfonic oxime 15 allowed for obtain- for obtaining
the
ing desired amine
the desired 9 (in9 the
amine form
(in the of hydrochloride)
form of hydrochloride) by reaction
by reaction with potassium
with potassium ethoxide
ethox-
hydrochloride;
ide hydrochloride; however, when it was released from the salt, it was very unstable and
however, when it was released from the salt, it was very unstable and
immediately
immediately decomposed,
decomposed, just just like
like diamine. The introduction
diamine. The introduction of of the
the CN
CN and
and NHCHO
NHCHO
functional
functional groups
groups into
into the
the C4
C4 position
position was was carried
carried out
out with
with low
low yields;
yields; the
the reaction
reaction of of
oxirane derivatives with amines gave a number of ketal and hydroxyamine
oxirane derivatives with amines gave a number of ketal and hydroxyamine derivatives derivatives
including
including 12, 13 (Scheme
12, 13 (Scheme 3). 3).
the other hand, conversion of ketone 5 to O-toluenesulfonic oxime 15 allowed for obtain-
ing the desired amine 9 (in the form of hydrochloride) by reaction with potassium ethox-
ide hydrochloride; however, when it was released from the salt, it was very unstable and
immediately decomposed, just like diamine. The introduction of the CN and NHCHO
functional groups into the C4 position was carried out with low yields; the reaction of
Molecules 2022, 27, 7322 9 of 56
oxirane derivatives with amines gave a number of ketal and hydroxyamine derivatives
including 12, 13 (Scheme 3).
Scheme3.3.Derivative
Scheme Derivativeproducts
productsstrategies
strategiesimplemented.
implemented.
Adding
Adding aa chain
chain atatthe
theC5
C5position
positionwas
wasexplored
exploredas asan
analternative
alternative totointroduction
introduction ofof
nitrogen at the C4 position. For this purpose, the Reformatsky reaction was
nitrogen at the C4 position. For this purpose, the Reformatsky reaction was carried out carried out with
the
withuse ofuse
the ketone 5. Treatment
of ketone of bromoacetate
5. Treatment in the in
of bromoacetate presence of zincofgave
the presence zincagave
hydroxyester,
a hydrox-
which on heating in formic acid gave an unsaturated ester. The ester
yester, which on heating in formic acid gave an unsaturated ester. The ester was was converted
convertedto
the bromoketone 16, which was then reduced to the oxirane 17. After using
to the bromoketone 16, which was then reduced to the oxirane 17. After using perbenzoic perbenzoic
acid,
acid,dioxide
dioxide18 18was
wasobtained,
obtained,which,
which,after
afterreacting
reactingwith
withthe
thebase,
base,gave
gavetetracyclic
tetracyclicdiol
diol1919
(Scheme 4).
(Scheme 4).
Scheme 4. Diol
Scheme4. 19 synthesis.
Diol 19 synthesis.
The
The obtained
obtained product
product probably
probably could
could be
be converted
converted into
into lysergic
lysergic acid,
acid, but
but the
the total
total
yield of nine steps (from ketone 5 to tetracycle 19) was so low that alternative
yield of nine steps (from ketone 5 to tetracycle 19) was so low that alternative paths were paths were
pursued.
pursued.
AA successful
successful synthetic
syntheticroute
route to
to lysergic acid. This
lysergic acid. This was
was achieved
achieved by by synthesizing
synthesizing thethe
unsaturated aldehyde 22 followed by the preparation of tertacyclic
unsaturated aldehyde 22 followed by the preparation of tertacyclic compounds. compounds.
This
This approach
approach waswas to
to convert
convert the
the ketone
ketone functional
functional group
group inin 55 into
into an
anunsaturated
unsaturated
aldehyde
aldehyde 22. To this end, a convergent synthesis leading to its preparation was developed
22. To this end, a convergent synthesis leading to its preparation was developed
using
usingDarzens
Darzensreaction
reaction[42],
[42], and
and then
then semicarbazide
semicarbazide substitution
substitution followed
followed by by replacement
replacement
with a pyruvic acid residue (Scheme 5).
pursued.
A successful synthetic route to lysergic acid. This was achieved by synthesizing the
unsaturated aldehyde 22 followed by the preparation of tertacyclic compounds.
This approach was to convert the ketone functional group in 5 into an unsaturated
aldehyde 22. To this end, a convergent synthesis leading to its preparation was developed
Molecules 2022, 27, 7322 10 of 56
using Darzens reaction [42], and then semicarbazide substitution followed by replacement
Scheme 5. Aldehyde
Scheme 5. 22 synthesis.
Aldehyde 22 synthesis.
Woodward
Woodwardproposed
proposedthree approaches
three approachesto synthesize an interesting
to synthesize intermediate.
an interesting One
intermediate.
of them turned out to be correct: the aldehyde 22 was converted to oxirane with
One of them turned out to be correct: the aldehyde 22 was converted to oxirane with hy- hydrogen
peroxide, then thethen
drogen peroxide, -CHO thegroup
-CHOwas reduced
group with NaBH
was reduced . Alcohol
with4NaBH 23 was reacted with
4. Alcohol 23 was reacted
methylaminoacetone–ethylene ketal and oxidized, and the product—ketone
with methylaminoacetone–ethylene ketal and oxidized, and the product—ketone 25 (Scheme 6)— 25
Molecules
Molecules2022,
2022,27,
27,xxFOR
FORPEER
PEERREVIEW
REVIEW 11
11 ofof 56
56
was isolated with the desired substituted amino group at C4 position. The disadvantage
(Scheme 6)—was isolated with the desired substituted amino group at C4 position. The of
this approach is
disadvantage ofthe
thislow yield due
approach to the
is the lowketal
yieldfragment attachment
due to the step. attachment step.
ketal fragment
Scheme
Scheme6.
Scheme 6.6.Ketone
Ketone2525synthesis.
25 synthesis.
However,
However,the
However, thereaction
the reaction
reaction ofof
the
of bromo
the
the bromo
bromosubstitution 4 with
substitution
substitution methylaminoacetone-ethylene
44 with
with methylaminoacetone-eth-
methylaminoacetone-eth-
ketal
ylenein
ylene a nonpolar
ketal
ketalin solvent
inaanonpolar
nonpolar was tested,
solvent
solvent was and product
wastested,
tested,and 25 (Scheme
andproduct
product 25 7) was
25(Scheme
(Scheme 7)obtained
7) was in two
wasobtained
obtained in
in
steps
two fromfrom
twosteps
steps ketone
from 4 in high
ketone
ketone 44in yield.
inhigh
highyield.
yield.
Scheme
Scheme7.7.Reaction
Reactionof
ofthe
thesubstitution
substitutionof bromine44with
ofbromine withketal.
ketal.
The
The last
Thelast step
laststep involvedclosing
stepinvolved
involved closingthe
closing theD-ring,
the D-ring,
D-ring, substitution
substitution
substitution of of
thethe
ofthe -COOH
-COOH
-COOH group,
group,
group, andand
and de-
de-
dehydrogenation
hydrogenation
hydrogenationof of
ofthe the starting
thestarting dihydroindole
startingdihydroindole structure.
dihydroindolestructure.
structure.
First,
First, protected
First,protected compound
protectedcompound
compound25 25 (Scheme
25(Scheme
(Scheme8)8) was
8)was hydrolyzed
washydrolyzed
hydrolyzedto to
toaaadiketone,
diketone,which
diketone, which was
whichwas
was
then
then cyclized.
thencyclized. Then,
cyclized.Then,
Then,α,β α,β unsaturated
α,βunsaturated carbonyl
unsaturatedcarbonyl
carbonyl3030 was
30was reduced
wasreduced with
reducedwith sodium
withsodium borohydride
sodiumborohydride
borohydride
to
to allyl
toallyl alcohol
allylalcohol
alcohol27.27.
27.
Optimization
Optimizationstudies
studieswere
wereperformed
performedaccording
accordingtotoPrice
Priceand andKrishnamurti,
Krishnamurti,which
which
described
describedthe
theconversion
conversionofofallyl
allylalcohol
alcoholto
toallyl
allylcyanide
cyanide[43].
[43].ItIthad
hadbeen
beenfound
foundthat
thatgood
good
results
resultscan
canbe
beachieved
achievedbybyforming
formingchloride
chloride2828followed
followedby
bynitrile
nitrile29
29using
usingsodium
sodiumcya-
cya-
nide
nidein
inanhydrous
anhydrousliquid
liquidhydrogen
hydrogencyanide.
cyanide.The
The-COOH
-COOHgroup
groupwas wasdisplaced
displacedby
bymeth-
meth-
Molecules2022,
Molecules 2022,27,
27,7322
x FOR PEER REVIEW 12
11 of 56
56
Scheme 8.
Scheme 8. Woodward
Woodwardpathway
pathwayto
tothe
thedeprotected
deprotectedkey
keyintermediate
intermediate2.2.
Optimization studies were performed according to Price and Krishnamurti, which

described the conversion of allyl alcohol to allyl cyanide [43]. It had been found that good
results can be achieved by forming chloride 28 followed by nitrile 29 using sodium cyanide
in anhydrous liquid hydrogen cyanide. The -COOH group was displaced by methanolysis
to an ester, followed by acidic or basic hydrolysis to compound 2.
The final challenge was the oxidation of the B-ring, while maintaining the D-ring double-
bond system. For this purpose, catalytic dehydrogenation on the Raney catalyst in the
presence
Scheme 8.ofWoodward
Scheme 9. sodium arsenate
Woodward pathway
pathwaywas
to used toacid.
to lysergic
the obtain key
deprotected target (±)-lysergic
the intermediate 2. acid (Scheme 9) [44].
The next part of this chapter presents syntheses using the key intermediate—herein-
after referred to as the Woodward intermediate (Figure 11), which is the ester 31 (PG—
protecting group). It is puzzling that Woodward did not receive the product 31. The name
of this intermediate was given by researchers in the following years.
The synthesis step in Scheme 8 shows the simultaneous methanolysis of the nitrile
group and deprotection of the amine, resulting in the product 2 being different from the
intermediate 31 by a protecting group. However, the key intermediate can be converted
into
Scheme
Scheme the9.9.product
Woodward
Woodward in apathway
mannertoto
pathway fully analogous
lysergic
lysergic acid. to the procedure outlined by Woodward—
acid.
lysergic acid 1 can be obtained from it by hydrolysis and dehydrogenation.
Parameters
The next part such as melting
of this chapterpoint, IR and
presents UV spectra,
syntheses using X-ray
the key powder diagrams, pKa,
intermediate—herein-
and
after referred to as the Woodward intermediate (Figure 11), which is theof
chromatographic analyses were investigated, confirming the structure the obtained
ester 31 (PG—
target product
protecting [45,46].
group). It is puzzling that Woodward did not receive the product 31. The name
In intermediate
of this summary, Woodward’s
was given by strategy was based
researchers in the on startingyears.
following from the indole dihydro
derivative, obtaining
The synthesis stepa tricyclic ketone,
in Scheme introducing
8 shows nitrogen atmethanolysis
the simultaneous the C4 position via nitrile
of the ketal,
cyclization to the tetracyclic system, hydrolysis of the -CN group, and
group and deprotection of the amine, resulting in the product 2 being different from thedehydrogenation of
the lysergic acid derivative to the target acid. Final yield based on
intermediate 31 by a protecting group. However, the key intermediate can be convertedcommercially available
substrate was 0.8%.
into the product in a manner fully analogous to the procedure outlined by Woodward—
lysergic acid part
The next 1 canofbe
this chapterfrom
obtained presents
it bysyntheses
hydrolysis using
andthe key intermediate—hereinafter
dehydrogenation.
referred to as the Woodward intermediate (Figure 11), which is the ester 31 (PG—protecting
group).
Figure 11.ItWoodward
is puzzling that Woodward
intermediate did not receive
31 and deprotected the product
compound 2. 31. The name of this
intermediate was given by researchers in the following years.
protecting group). It is puzzling that Woodward did not receive the product 31. The name
of this intermediate was given by researchers in the following years.
Molecules 2022, 27, 7322 into the product in a manner fully analogous to the procedure outlined by Woodward—12 of 56
Woodward intermediate
Figure 11. Woodward 31 and
intermediate 31 and deprotected
deprotected compound
compound 2.
2.
into the product in a manner fully analogous to the procedure outlined by Woodward—
2.1.2.Baillarge
2.1.2. BaillargeGroup
GroupResearch
Research
Thelysergic
The lysergicacid
acidsynthesis
synthesisperformed
performedby byM.M.Julia
Juliaononthe
theBaillarge
Baillargeteam
team[47]
[47]uses
usesthe
the
preparationofofa atricyclic
preparation tricyclic system
system obtained
obtained as as a result
a result of the
of the condensation
condensation of 5-bromoisatin
of 5-bromoisatin 32
32 and
and methyl
methyl 6-methylnicotinate
6-methylnicotinate 33. 33. A key
A key reaction
reaction waswas aryne
aryne cyclization.The
cyclization. Thesynthesis
synthesis
wasstarted
was startedbybyobtaining
obtainingisatin
isatinnicotinate
nicotinate34.34.Thereafter,
Thereafter,reduction
reductionofofthe
thedouble
doublebond
bondwas
was
performed
performedby bytreatment
treatmentwith withzinc in in
zinc acetic acid
acetic as as
acid well as reduction
well with
as reduction diborane
with to obtain
diborane to ob-
atain
saturated indoline
a saturated system.
indoline The amine
system. The aminewas was
protected by acetylation
protected to give
by acetylation product
to give 35
product
(Scheme
35 (Scheme10). 10).
Scheme10.
Scheme 10.Beginning
Beginningofofthe
thesynthesis
synthesisproposed
proposedby
byBaillarge
Baillargeteam.
team.
In
Inthe
thenext
nextstep,
step,methyl
methyliodide
iodidewaswasadded
addedtotocompound
compound35, 35,followed
followedby bypotassium
potassium
borohydride,
borohydride,whereby
wherebythe aromatic
the aromatic pyridine ring
pyridine waswas
ring reduced
reducedto α,β-unsaturated
to α,β-unsaturated esterester
37.
It37.
wasIt noted that athat
was noted mixture of twoof
a mixture diastereoisomers differing
two diastereoisomers in physicochemical
differing parameters
in physicochemical pa-
was obtained.
rameters After the use
was obtained. ofthe
After sodium
use ofamide,
sodium inamide,
ammonia in the reflux,
in ammonia in thethe cyclization
reflux, the cy-
reaction was only observed for the (S)-isomer, with a yield of 36%. The product
clization reaction was only observed for the (S)-isomer, with a yield of 36%. The product methyl
N-acetyl-2,3-dihydrolysergate was isolated,
methyl N-acetyl-2,3-dihydrolysergate waswhich waswhich
isolated, in fact was
an Ac-protected Woodward
in fact an Ac-protected
intermediate (R)-31 (Scheme 11).
Woodward intermediate (R)-31 (Scheme 11).
Using the Woodward and Kornfeld procedure [31,32], this compound can be converted
into lysergic acid 1, which formally ends the synthesis. After examining the IR, UV, and
mass spectra and preparing a TLC analysis in various systems, to compare the product
with the intermediate obtained by Woodward, the identity of the obtained compound was
confirmed.
In the next step, methyl iodide was added to compound 35, followed by potassium
borohydride, whereby the aromatic pyridine ring was reduced to α,β-unsaturated ester
37. It was noted that a mixture of two diastereoisomers differing in physicochemical pa-
rameters was obtained. After the use of sodium amide, in ammonia in the reflux, the cy-
clization reaction was only observed for the (S)-isomer, with a yield of 36%. The product
Molecules 2022, 27, 7322 13 of 56
methyl N-acetyl-2,3-dihydrolysergate was isolated, which was in fact an Ac-protected
Woodward intermediate (R)-31 (Scheme 11).
Scheme11.
Scheme 11.Synthesis
Synthesisof
ofthe
theprotected
protectedWoodward’s
Woodward’sintermediate.
intermediate.
2.1.3. Using
Ramage’s
the Research
Woodward Group
and Kornfeld procedure [31,32], this compound can be con-
verted into lysergic
R. Ramage, acid 1, which
W. Armstrong, formally
and ends in
S. Coulton, the1981,
synthesis. After
used and examining
improved the IR, UV,
Woodward’s
and mass
strategy spectra
[32]. and preparing
Optimization of thea TLC analysis
synthesis in various
of tricyclic systems,22,
aldehyde to which
compare thethen
was prod-
a
uct with the
substrate, in intermediate obtained
order to obtain by Woodward,
Woodward’s the identity
intermediate 31, wasof the obtained
performed. compound
A procedure
was
wasproposed,
confirmed.which consisted of passing through the Wittig reaction to the unsaturated
diester 38 and then introducing the amino group using the Curtius degradation procedure
and cyclization of the D ring.
In the work of the Ramage group, a lot of emphasis was placed on structures and inter-
mediates through the analysis of NMR spectra, which confirmed the reaction mechanism
proposed in the first synthesis. In addition to NMR studies, HPLC chromatogram was
also investigated as were the crystallographic analyses and UV/IR spectra of the products.
Thanks to these studies, it was found that lysergic acid formed as two epimers, and their
ratio was determined.
Aldehyde 22 (having a well-described, two-step synthetic pathway via semicarbazide
in the experimental part) [32], was converted with a Wittig reaction through resonance-
stabilized ylide into an unsaturated diester 38. The reaction is stereospecific (configuration
E), because the Wittig reaction with resonance stabilized ylides leads to systems having a
carbonyl trans function to a larger group at the beta position [48]. Then, chemoselective
hydrolysis of the ester bond of the -COOtBu group was carried out, and the Curtius
degradation procedure was optimized (the total efficiency of this procedure was 80% [49]);
at the beginning, tetramethylguanidine azide and mixed diphenylphosphinic anhydride
were added to a diester 38, and thermal rearrangement took place. Azide to the isocyanate
39 was performed, followed by hydration and decarboxylation to the amine. To avoid side
reactions, it was decided to control the hydration using tosylic acid monohydrate. Thus,
the amino group was introduced into compound 40 as a protected tosyl salt (Scheme 12).
Secondary amines have been shown to cyclize much more easily than primary amines [50].
The Woodward reaction mechanism model also assumes that the amine is an intermediate,
spontaneously cyclizing to a 2,3-dihydrolysergic system [33,51]. Therefore, the Eschweiler–
Clarke reaction [52,53] was performed with HCOOH/HCHO, yielding three tetracyclic
products ((R)-31, (S)-31, 41) in a 9:3:2 ratio, from which two Woodward intermediate epimers
(R/S)-31 were separated. The use of boiling methanol allowed for the epimerization of the
isolysergic acid related compound (S)-31 to the lysergic derivative (R)-31 (Scheme 13).
degradation procedure was optimized (the total efficiency of this procedure was 80%
[49]); at the beginning, tetramethylguanidine azide and mixed diphenylphosphinic anhy-
dride were added to a diester 38, and thermal rearrangement took place. Azide to the
isocyanate 39 was performed, followed by hydration and decarboxylation to the amine.
To avoid side reactions, it was decided to control the hydration using tosylic acid mono-
Molecules 2022, 27, 7322 14 of 56
hydrate. Thus, the amino group was introduced into compound 40 as a protected tosyl
salt (Scheme 12).

Scheme12.
Scheme 12.First
Firstpart
partof
ofthe
theRamage
Ramagesynthesis.
synthesis.
Secondary amines have been shown to cyclize much more easily than primary
amines [50]. The Woodward reaction mechanism model also assumes that the amine is an
intermediate, spontaneously cyclizing to a 2,3-dihydrolysergic system [33,51]. Therefore,
the Eschweiler–Clarke reaction [52,53] was performed with HCOOH/HCHO, yielding
three tetracyclic products (R)-31, (S)-31, 41) in a 9:3:2 ratio, from which two Woodward
intermediate epimers (R/S)-31 were separated. The use of boiling methanol allowed for
the epimerization of the isolysergic acid related compound (S)-31 to the lysergic deriva-
tive (R)-31 (Scheme 13).
Scheme 13. Second part of the Ramage synthesis.
Pure
Scheme compound
13. Second
Secondpart (R)-31
partof
of was treated
theRamage
Ramage with HCl in MeOH to yield debenzylated epi-
synthesis.
Scheme 13. the synthesis.
meric lysergic acid derivatives (R)-2 and (S)-2 in a 5:2 ratio (Scheme 14). These products
werePure
identical
Pure to the(R)-31
compound
compound material
(R)-31was used
was in the
treated
treated first
with
with HClWoodward
HCl in MeOH
in MeOH lysergic
to aciddebenzylated
to yield
yield synthesisepimeric
debenzylated [31].epi-
As
a result of
meric lysergic
lysergic further work of the
acid derivatives
acid derivatives team,
(R)-2
(R)-2 and derivatives
andin(S)-2
(S)-2 were
a 5:2inratio also obtained,
a 5:2(Scheme
ratio (Scheme which were
14). These
14). These secondary
products
products were
and not
were
identical tertiary
identical
to to amines
the material in the
the material
used D ring,
inused
the in the
first enabling their
first Woodward
Woodward further
lysergic acid functionalization
lysergic [31]. As towards
acid synthesis
synthesis a[31]. As
result
ainteresting
of further
result ofworkderivatives.
of work
further the team, derivatives
of the were alsowere
team, derivatives obtained, which were
also obtained, secondary
which and not
were secondary
Treating
tertiary
and not amines the
tertiary Curtius
inamines
the inprocedure
D ring, enabling
the D ring, astheir
a single one-pot
further
enabling reaction,
functionalization
their further thetowards
transition
functionalization from
interesting
towards ke-
tone to Woodward
derivatives.
interesting derivatives. intermediate consists of four reactions [54].
Treating the Curtius procedure as a single one-pot reaction, the transition from ke-
tone to Woodward intermediate consists of four reactions [54].
Scheme14.
Scheme 14.Obtained
Obtainedepimers
epimersof
ofdihydrolysergic
dihydrolysergicacid
acidderivatives
derivatives2.2.
2.1.4.Treating
Scheme Rebek’s Research
the Curtius
14. Obtained Group
procedure
epimers as a singleacid
of dihydrolysergic one-pot reaction,
derivatives 2. the transition from ketone
to Woodward intermediate
Rebek’s team proposed consists of foursimple
a different, reactions [54]. material for the preparation of
starting
2.1.4. Rebek’s Research Group
lysergic acid, which is the natural amino acid tryptophan 42 [55,56]. The first part involved
obtaining theteam
Rebek’s tricyclic ketone,aanalogous
proposed different, to the Woodward
simple path [31].
starting material forAmino acid deriva-
the preparation of
tive Rebek’s
42 was
lysergic
team proposed
acid,converted
which is the
a different,
to natural
ketone 44 by
amino
simple
addingstarting
aceticmaterial
acid tryptophan
for the
anhydride and
42 [55,56].
preparation of chloride
Thealuminum
lysergic
first part involved
acid, which
(Scheme is the natural amino acid tryptophan 42 [55,56]. The first part involved obtaining
15).
obtaining the tricyclic ketone, analogous to the Woodward path [31]. Amino acid deriva-
the tricyclic ketone, analogous to the Woodward path [31]. Amino acid derivative 42 was
tive 42 was converted to ketone 44 by adding acetic anhydride and aluminum chloride
converted to ketone 44 by adding acetic anhydride and aluminum chloride (Scheme 15).
(Scheme 15).
Rebek’s team proposed a different, simple starting material for the preparation of
lysergic acid, which is the natural amino acid tryptophan 42 [55,56]. The first part involved
obtaining the tricyclic ketone, analogous to the Woodward path [31]. Amino acid deriva-
Molecules 2022, 27, 7322 15 of 56
tive 42 was converted to ketone 44 by adding acetic anhydride and aluminum chloride
(Scheme 15).
Scheme15.
Scheme 15. Preparation
Preparationof
ofthe
theRebek
Rebeksubstrate
substrate44.
44.
The
The obtained
obtained ketone
ketone isis functionalized
functionalized byby using
using the
the starting
starting amino
amino acid—it
acid—it has
has an
an
amino
aminofragment
fragmentin inthe
theC4C4position.
position.
The
The next
next steps
steps involved
involved closing
closing the
the D
D ring.
ring. Initially,
Initially, ketone 44 was
ketone 44 was converted
converted into
into
spiro-lactone 45, giving methylated compound 46 in the presence of sodium
spiro-lactone 45, giving methylated compound 46 in the presence of sodium hydride and hydride and
methyl
methyliodide,
iodide,which
whichwaswas hydrobrominated
hydrobrominatedand andthen
thenclosed
closedininthe
the three-stage
three-stageHenessian
Henessian
sequence
sequence[57]
[57]into
intothe
thepentacyclic
pentacyclicstructure
structureofofthe
thelactone
lactone4949(Scheme
(Scheme16).16).
Scheme16.
Scheme 16. The
Thefirst
firstpart
partof
ofRebek
Rebeksynthesis.
synthesis.
The
The last wasthe
last part was theformation
formationofofanan ester
ester group
group andand dehydration
dehydration to lysergic
to the the lysergic
acid
acid structure.
structure. Lactone
Lactone 49 was was opened
49 opened with thionyl
with thionyl chloride
chloride to dihydrochloride
to dihydrochloride ester
ester 50, 50,
which
which was dehydrated
was dehydrated to 2.
to olefin olefin 2. Oxidation
Oxidation under
under mild mild conditions
conditions made it made
possibleit possible
to obtaintoa
obtain
mixturea mixture of deprotected
of deprotected isolysergic
isolysergic and lysergic
and lysergic acid
acid esters 51esters 51 (Scheme
(Scheme 17), the
17), the physico-
physicochemical
chemical parameters of which were consistent with the data in the literature [58]. [58].
parameters of which were consistent with the data in the literature
Scheme17.
Scheme 17. The
Thesecond
secondpart
partof
ofRebek
Rebeksynthesis.
synthesis.
2.1.5.
2.1.5. Kiguchi’s
Kiguchi’s Research
ResearchGroup
Group
The
The Kiguchi group proposed, in
Kiguchi group proposed, in 1982,
1982, the
the synthesis
synthesis of
of the
the Woodward
Woodwardintermediate
intermediate
using the photochemical cyclization reaction of the D ring [59].
using the photochemical cyclization reaction of the D ring [59].
This work is an interesting attempt to obtain an optically pure intermediate. The orig-
inal Woodward article [31] did not focus on obtaining pure chiral products. Instead, the
lysergic acid that formed was a racemic mixture. The chirality of the intermediates was
not tested either—as in Rebek’s work [55], a mixture of four final ester stereoisomers was
Molecules 2022, 27, 7322 16 of 56
This work is an interesting attempt to obtain an optically pure intermediate. The

original Woodward article [31] did not focus on obtaining pure chiral products. Instead,
the lysergic acid that formed was a racemic mixture. The chirality of the intermediates was
not tested either—as in Rebek’s work [55], a mixture of four final ester stereoisomers was
obtained. Therefore, this procedure is linked to the Ramage article [32].
The synthesis started with a more complicated structure than proposed by Wood-
ward or Rebek—with the tricyclic ketone (benzo(f)quinoline derivative) described in the
literature 52 [60,61]. Known ketone 52 was treated with methylamine to give imine 53 as
an intermediate, which was easily converted to enamide 54 after acylation with 3-furoyl
Molecules
Molecules 2022,
2022, 27,
27, xx FOR
FOR PEER
PEER REVIEW
REVIEW
chloride in the presence of triethylamine. Reductive photocyclization was performed, 17
17 of
of 56
56
leading to lactam 55 (Scheme 18).
Scheme
Scheme 18.The
Scheme18.
18. Thefirst
The firstpart
first partof
part ofKiguchi
of Kiguchisynthesis.
Kiguchi synthesis.
synthesis.
Reduction
Reduction of
Reduction oflactam
of lactam55
lactam 55with
55 withLiAlH
with LiAlH444 followed
LiAlH followed by
followed by reprotection
by reprotection of
reprotection of the
of the amine
the amine gave
amine gaveaaa
gave
mixture
mixture of
mixture of two
of two diastereoisomers
two diastereoisomers 56
diastereoisomers 56 (Scheme
56 (Scheme 19).
(Scheme 19). The
19). The decarbonylated
The decarbonylated amine
decarbonylated amine (R)-56,
amine (R)-56, having
(R)-56, having
having
the
thestereochemistry
the stereochemistrycorresponding
stereochemistry correspondingto
corresponding to thed-(+)-configuration
tothe
the d-(+)-configurationof
d-(+)-configuration oflysergic
of lysergicacid,
lysergic acid,was
acid, wasisolated
was isolated
isolated
by
bycrystallization.
by crystallization.
crystallization.
Scheme 19.
Scheme19.
Scheme The
19.The second
Thesecond part
secondpart of
partof Kiguchi
ofKiguchi synthesis.
Kiguchisynthesis.
synthesis.
Oxidation
Oxidationof
Oxidation ofamine
of amine (R)-56gave
amine(R)-56
(R)-56 gaveglycol
gave glycol 57,which
glycol57,
57, whichis
which isaaadiastereomeric
is diastereomericmixture
diastereomeric mixtureof
mixture oftwo
of two
two
cis-glycols.
cis-glycols. Without
cis-glycols. Without further
further purification,
purification, oxidation
purification, oxidation ofof the
the glycol
the glycolwith
glycol withsodium
with sodiumperiodate
sodium periodate
periodate
gave
gaveaaamixture
gave mixtureof
mixture ofepimeric
of epimerichydroxyaldehydes
epimeric hydroxyaldehydes58
hydroxyaldehydes 58(Scheme
58 (Scheme20)
(Scheme 20)[59].
20) [59].
[59].
Scheme
Scheme 20.
20. The
The third
third part
part of
of Kiguchi
Kiguchi synthesis.
synthesis.
After
After oxidation
oxidation of
of hydroxyaldehydes
hydroxyaldehydes toto hydroxyesters,
hydroxyesters, itit was
was investigated
investigated that
that the
the
products
products contain
contain two
two epimers,
epimers, which
which are
are precursors
precursors of
of isolysergic
isolysergic (S)-59
(S)-59 and
and lysergic
lysergic (R)-
(R)-
Scheme 19. The second part of Kiguchi synthesis.
Oxidation of amine (R)-56 gave glycol 57, which is a diastereomeric mixture of two
Molecules 2022, 27, 7322 17 of 56
cis-glycols. Without further purification, oxidation of the glycol with sodium periodate
gave a mixture of epimeric hydroxyaldehydes 58 (Scheme 20) [59].
Scheme20.
Scheme 20.The
Thethird
thirdpart
partof
ofKiguchi
Kiguchisynthesis.
synthesis.
After
Afteroxidation
oxidation ofofhydroxyaldehydes
hydroxyaldehydes to to hydroxyesters,
hydroxyesters, itit was
wasinvestigated
investigated that
that the
the
products
products contain epimers,which
contain two epimers, whichare
areprecursors
precursorsof of isolysergic
isolysergic (S)-59 andand
(S)-59 lysergic
lysergic (R)-
(R)-59 acids.
59 acids. Dehydration
Dehydration of both
of both hydroxyesters
hydroxyesters gaveproduct—unsaturated
gave one one product—unsaturated ester
ester (R)-31,
(R)-31, which is an optically pure Woodward intermediate (Scheme 21). This
which is an optically pure Woodward intermediate (Scheme 21). This selectivity is due to selectivity
isthe
Molecules 2022, 27, x FOR PEER REVIEW due to thethermodynamic
higher higher thermodynamic
stabilitystability of β-equatorial
of β-equatorial esters relative
esters relative to the to the α-axial
α-axial 18esters
of 56
esters [33,51]. Spectral examination confirmed the identity of structure
the structure to the 18
compoundof 56
[33,51]. Spectral examination confirmed the identity of the to the compound ob-
obtained
tained byby Ramage
Ramage [32]
[32] and
and Woodward[31].
Woodward [31].
Scheme 21. The last part of Kiguchi synthesis.

Scheme21.
Scheme 21.The
Thelast
lastpart
partof
ofKiguchi
Kiguchisynthesis.
synthesis.
Continuing the work of the team, during the first synthesis of (±)-isofumigaclavine B
Continuing
Continuing
in 1985 thework
the workof
[62], the synthesis oflysergic
of theteam,
the team, during
during
acid was the thefirst
first
almost synthesisofRemoval
synthesis
completed. of(±
(±)-isofumigaclavine
)-isofumigaclavine
of Bz protectingBB
in1985
in 1985[62],
group [62],the
and thesynthesis
synthesis
oxidation of
of of lysergic
lysergic
mixed acidwas
acid
epimers was almost
of almost completed.
completed.
ester (31) Removal
Removal
produced lysergicofBz
of Bz protecting
acidprotecting
ester 51
group
group and
and
(Scheme oxidation
oxidation
22). of mixed
of mixed epimers
epimers of esterof(31)
ester (31) produced
produced lysergic
lysergic acid acid
ester 51 ester 22).
(Scheme 51
(Scheme 22).
Scheme22.
Scheme 22.Additional
AdditionalKiguchi
Kiguchiresearch.
research.
Scheme 22. Additional Kiguchi research.
Theuse
The useofofthe
thephotochemical
photochemicalcyclization
cyclization reaction
reactionisisan aninteresting
interestingalternative
alternativeto
tothe
the
Theproposals
previous
previous use of thefor
proposals photochemical
forthe
theclosing cyclization
closingofof
the
theD-ring.
D-ring.reaction a is an interesting
ItItisisa completely
completely fresh alternative
approach,
fresh approach, to
usingthe
usinga
previous
different proposals
branch of for
chemicalthe closing of
synthesis. the
ThisD-ring.
work It
was is a
an completely
important fresh
step
a different branch of chemical synthesis. This work was an important step towards ob- approach,
towards using
obtaining
ataining
puredifferent
chiral
pure branch
chiral of
d-lysergic chemical
acid.
d-lysergic synthesis. This work was an important step towards ob-
acid.
taining pure
According chiral
According to tothed-lysergic
thelatest acid.
latestreports,
reports,structure
structure 5151can
canalso alsobebeobtained
obtainedininthree–five
three–fivesteps
steps
fromaAccording
from anicotinic to
nicotinicacid the
acid latest
ester
ester 60reports,
60 (Schemestructure
(Scheme 23) [63]. 51 can also be obtained in three–five steps
23)[63].
from a nicotinic acid ester 60 (Scheme 23) [63].
Scheme 23. A new method for the synthesis of compound 51.

Scheme 23. A new method for the synthesis of compound 51.
2.2. Hendrickson’s Strategy
2.2. Hendrickson’s Strategy
2.2.1. Direct Hendrickson’s Research
The use of the photochemical cyclization reaction is an interesting alternative to the
previous proposals for the closing of the D-ring. It is a completely fresh approach, using
a different branch of chemical synthesis. This work was an important step towards ob-
taining pure chiral d-lysergic acid.
Molecules 2022, 27, 7322 18 of 56
According to the latest reports, structure 51 can also be obtained in three–five steps
from a nicotinic acid ester 60 (Scheme 23) [63].
Scheme23.
Scheme 23. A
A new
newmethod
methodfor
forthe
thesynthesis
synthesisof
ofcompound
compound51.
51.
2.2.
2.2. Hendrickson’s
Hendrickson’sStrategy
Strategy
Hendrickson’s group approached the topic of lysergic acid synthesis from a new angle.
Hendrickson’s group approached the topic of lysergic acid synthesis from a new an-
Using readily available components such as an indole halide and a pyridine derivative, they
gle. Using readily available components such as an indole halide and a pyridine deriva-
obtained the lysergic acid structure using a coupling reaction followed by cyclization of the
tive, they obtained the lysergic acid structure using a coupling reaction followed by cy-
aldehyde to give the D ring—the key Hendrickson intermediate [64]. The desired product
clization of the aldehyde to give the D ring—the key Hendrickson intermediate [64]. The
was then obtained by reduction with a classical borohydride. The main advantage of this
desired product was then obtained by reduction with a classical borohydride. The main
approach is the convergence and simplicity of the method, as well as the total efficiency.
advantage of this approach is the convergence and simplicity of the method, as well as the
The product was obtained in eight steps, and the yield was 10.6%.
totalTheefficiency. The product
assumptions was obtained
of the strategy in eight
proposed steps, and theare:
by Hendrickson yield was 10.6%.
synthesis of lysergic
The assumptions of the strategy proposed by Hendrickson are:
acid through the shortest possible path, without protection of the indole fragment, synthesis of lysergic
and
acid
Molecules 2022, 27, x FOR PEER REVIEW through the shortest possible path,
introduction of the D ring through Suzuki coupling. without protection of the indole fragment, and
19 of 56
introduction of the D ring through Suzuki coupling.
The synthesis was started with the preparation of the halogen derivative of indole
The synthesis
61, which was started
was converted with the preparation
into compound of thethe
62. Starting from halogen derivative
dicarboxylic of indole
derivative of
61, which
pyridine was
63, the converted
synthesis into
of its compound
N-oxide was62. Starting
performed, from
and the
then,dicarboxylic
with thionylderivative
chloride, of
it
pyridine 63, the synthesis of its N-oxide was performed, and then, with thionyl chloride,
was converted into a chlorine derivative of 64 (interestingly, only under these conditions
it was converted into a chlorine derivative of 64 (interestingly, only under these conditions the
meta derivative
the meta is obtained,
derivative instead
is obtained, of theof
instead classic ortho/para
the classic substitution).
ortho/para The aromatic
substitution). The aro-
substrates, thus prepared, were easily coupled via a palladium-catalyzed
matic substrates, thus prepared, were easily coupled via a palladium-catalyzed Suzuki reaction
Suzuki
toreaction
the tricyclic
to the derivative 65 (Scheme
tricyclic derivative 24). An24).
65 (Scheme analogous coupling
An analogous was simultaneously
coupling was simultane-
described by Dollby
ously described [65].
Doll [65].
Scheme24.
Scheme 24.Coupling
Couplingreaction
reactionleading
leadingtotoaatricyclic
tricyclicsystem
system65.
65.
Closingthe
Closing thetetracyclic
tetracyclic system
system posed
posed some
some difficulties—diester
difficulties — diester6565did
didnot
notgive
givethe
the
expectedcyclization
expected cyclizationproduct;
product;therefore,
therefore,the
theester
esterwas
wasreduced
reducedtotoalcohol
alcoholand
andthen
thengently
gently
oxidizedtotoactive
oxidized activealdehyde
aldehyde66, 66,which,
which,under
underbasic
basicconditions,
conditions,resulted
resultedininaatertiary
tertiarycyclic
cyclic
alcohol67,
alcohol 67,known
knownasasHendrickson’s
Hendrickson’sintermediate
intermediate(Scheme
(Scheme25).
25).
Scheme 25. Obtaining Hendickson’s intermediate.
Reduction of the alcohol 67, N-methylation of the pyridine derivative and reduction
of the aromatic system were performed to obtain a mixture of 69: lysergic acid ester and
Scheme 24. Coupling reaction leading to a tricyclic system 65.
Scheme 24. Coupling reaction leading to a tricyclic system 65.
Closing the
Closing the tetracyclic
tetracyclic system
system posed
posed some
some difficulties
difficulties —
— diester
diester 65
65 did
did not
not give
give the
the
expected cyclization product; therefore, the ester was reduced to alcohol and then
expected cyclization product; therefore, the ester was reduced to alcohol and then gently gently
Molecules 2022, 27, 7322 oxidized to
to active
active aldehyde
aldehyde 66,
66, which,
which, under
under basic
basic conditions,
conditions, resulted
resulted in
in aa tertiary
tertiary19cyclic
cyclic
of 56
oxidized
alcohol 67,
alcohol 67, known
known as as Hendrickson’s
Hendrickson’s intermediate
intermediate (Scheme
(Scheme 25).
25).
Scheme 25. Obtaining Hendickson’s intermediate.

Scheme 25.
Scheme 25. Obtaining
Obtaining Hendickson’s
Hendickson’s intermediate.
intermediate.
Reductionof
Reduction
Reduction ofthe
of thealcohol
the alcohol67,
alcohol 67,N-methylation
67, N-methylationof
N-methylation ofthe
of thepyridine
the pyridinederivative
pyridine derivativeand
derivative andreduction
and reduction
reduction
of
of the
of the aromatic
the aromatic system
aromatic system
system were were performed
were performed
performed to to obtain
to obtain a mixture
obtain aa mixture
mixture of of 69: lysergic
69: lysergic
of 69: acid
lysergic acid esterand
acid ester
ester and
and
isolysergic acid
isolysergic
isolysergic acid ester
acid ester in
ester in aaaratio
in ratioof
ratio of6:1
of 6:1(Scheme
6:1 (Scheme26).
(Scheme 26). The
26). The last
The last three
last three steps
three stepswere
steps wereperformed
were performed
performed
without
without isolation to avoid losses due to product instability. Using
without isolation to avoid losses due to product instability. Using the procedure from
isolation to avoid losses due to product instability. Using the
the procedure
procedure fromthe
from the
the
literature
literature on
on the
the isomerization
isomerization of
of the
the iso-lysergic
iso-lysergic acid
acid form,
form, it
it was
was converted
converted
literature on the isomerization of the iso-lysergic acid form, it was converted to the desired to
to the
the desired
desired
acidunder
acid
acid underbasic
under basicconditions.
basic conditions. Its
conditions. Its physicochemical
Its physicochemical properties
physicochemical properties such
properties such as
such as melting
as melting point
melting point were
point were
were
checked
checked
checked to to confirm
to confirm
confirmits its structure.
itsstructure.
structure.
2.2.2. Problems Noticed by Bekkam

In 2011, Bekkam, Mo, and Nichols [66] repeated the synthesis of lysergic acid using
the conditions proposed by Hendrickson [64], using methyl esters 70. Surprisingly, it
turned out that the cyclization step to compound 67, as shown in Scheme 25, did not occur.
SchemeThe26.reaction
Synthesiswas attempted
of lysergic acidmultiple times;byneither
ester proposed the change of researcher nor the
Hendrickson.
Scheme
Scheme 26.26. Synthesis
Synthesis ofof lysergic
lysergic acid
acid ester
esterproposed
proposedby byHendrickson.
Hendrickson.
multiple repetitions of the reactions with different amounts of base, different time, and
different temperatures
However,
However, this
thispathwayresulted
pathway of in the desired
ofobtaining
obtaining effect.
lysergic
lysergic acidThe
acid was
wasobtained
provencompound
proven to
tobebenot 71 was the
notfeasible,
feasible, as
as
However, this pathway of obtaining lysergic acid was proven to be not feasible, as
product
described
described of the
later
later cyclization
ininthis
this and
chapter.
chapter. aromatization of the system (Scheme 27).
described later in this chapter.
The structure was unambiguously checked and determined by melting point and the
2.2.2. Problems
analysis of one- Noticed by Bekkam
and two-dimensional NMR spectra (1H, 13C, COSY, HMBC, TCOSY,
In 2011, Bekkam, Mo, and Nichols [66] repeated the synthesis of lysergic acid using the
HMQC).
conditions proposed
The reason by Hendrickson
for obtaining the other[64],
mainusing methyl
product esters
is the 70. Surprisingly,
resonance it turned
stabilization of the
out that the cyclization
indoquinoline system, step to compound
as well as the fact67, as the
that shown in Scheme
dihedral angle25, did not the
between occur.
carbonyl
Theand
carbon reaction
the C3was attempted
carbon is 160°, multiple times;
which allows forneither the changeunder
easy elimination of researcher nor the
basic conditions
multiple repetitions of
according to the E2 mechanism.the reactions with different amounts of base, different time, and
different temperatures
Researchers have resulted
not beeninablethe to
desired
contact effect. The obtained
members compound
of Hendrickson’s 71 wasbut
group, theit
product
must beof the cyclization
assumed that thisand aromatization
particular path is ofnotthe system (Scheme 27).
feasible.
Scheme 27.
Scheme 27. Structural
Structuralformula
formulaofofthe
theproduct obtained
product in the
obtained literature
in the procedure
literature repeated
procedure by Bek-
repeated by
kam.
Bekkam.
However,
The before
structure wasthese problems were
unambiguously noticed
checked andby Bekkam, Hendrickson’s
determined strategy
by melting point and
wasanalysis
the used toofformally synthesize
one- and lysergic acid
two-dimensional NMR byspectra 1
Yigang(Zhao13
H, [67] and Beaundry
C, COSY, [68].
HMBC, TCOSY,
HMQC).
2.2.3. Yigang Zhao Work
Yigang Zhao’s doctoral dissertation from the Snieckus group presents an alternative
method of obtaining the key Hendrickson intermediate [67,69]. Selective amidation, DoM
(Directed Orto Metalation-Suzuki cross coupling) cross coupling, and the chemoselective
Molecules 2022, 27, 7322 20 of 56
The reason for obtaining the other main product is the resonance stabilization of the
indoquinoline system, as well as the fact that the dihedral angle between the carbonyl
Schemeand
carbon 27. Structural formula
the C3 carbon is 160 ◦ , which
of the product obtained
allows in theelimination
for easy literature procedure repeated
under basic by Bek-
conditions
kam.
according to the E2 mechanism.
Researchers have not been able to contact members of Hendrickson’s group, but it
must However,
be assumed before these
that this problems
particular were
path noticed
is not by Bekkam, Hendrickson’s strategy
feasible.
was However,
used to formally synthesize lysergic acid by Yigang
before these problems were noticed by Bekkam, ZhaoHendrickson’s
[67] and Beaundry [68].
strategy was
used to formally synthesize lysergic acid by Yigang Zhao [67] and Beaundry [68].
2.2.3. Yigang Zhao Work
2.2.3. Yigang
Yigang Zhao’s
Zhao Work
doctoral dissertation from the Snieckus group presents an alternative
Yigang
method Zhao’s doctoral
of obtaining the keydissertation
Hendrickson from the Snieckus
intermediate group
[67,69]. presents
Selective an alternative
amidation, DoM
method
(Directed of Orto
obtaining the key Hendrickson
Metalation-Suzuki intermediate
cross coupling) cross[67,69].
coupling,Selective
and theamidation, DoM
chemoselective
(Directed
reductionOrtoof anMetalation-Suzuki
amide to an aldehydecross using
coupling) cross coupling,
Schwartz’s reagent and
werethe chemoselective
used for this pur-
reduction
pose. Thisofsimplifies
an amideHendrickson’s
to an aldehydestrategy
using Schwartz’s reagent
by eliminating were
one used
step.. for this
Then, purpose.
according to
This simplifiesinHendrickson’s
the reactions strategy
the literature, the by eliminating
compound one step. and
can be deprotected Then, according
cyclized [64]. to the
reactions
The in thestep
first literature, the compound
was selective amidation canandbetransesterification
deprotected and cyclized
to 73. The[64].
substrate pre-
paredThein first step can
this way wasbeselective
coupledamidation and transesterification
using the conditions optimized bytothe The substrate
73.researchers for a
prepared in this way can be coupled using the conditions optimized by
tricyclic system 74 (Scheme 28). The reduction step with the use of an organozirconium the researchers
for a tricyclic
reagent tooksystem 74 (Scheme
place after 28). The
protection reduction
of the step with
indole N-H; the useBoc-protection
therefore, of an organozirconium
was pro-
reagent
posed. took place after protection of the indole N-H; therefore, Boc-protection was proposed.
Scheme28.
Scheme 28. Coupling
Couplingreaction
reactionleading
leadingto
toaaprotected
protectedtricyclic
tricyclicsystem
system74.
74.
Carrying
Carrying outout the
the reduction
reduction with
with the
the Schwartz
Schwartz reagent
reagent allows
allows for
for obtaining
obtaining the
the alde-
alde-
hyde in an efficient manner, even in the presence of a more reducible ester. It
hyde in an efficient manner, even in the presence of a more reducible ester. It was postu-was pos-
tulated
lated (dotted arrow) that in this way, after carrying out two steps, it could lead to the
(dotted arrow) that in this way, after carrying out two steps, it could lead to the
Hendrickson’s
intermediate67 67(Scheme
(Scheme29).
29).
Scheme 29.
Scheme 29. Synthetic
Synthetic path
path leading
leading to
to the
the Henrickson’s
Henrickson’sintermediate,
intermediate,as
aspostulated
postulatedby
byYigang.
Yigang.
This
This modification
modificationmakes makesititpossible
possibleto
toobtain
obtainthe
the intermediate
intermediatein
in six,
six, instead
instead of
of seven
seven
steps,
steps, but
but itit involves
involves the
theuse
useof
oforganometallic
organometallicreagents
reagentssuch
suchas
asBuLi
BuLiand
andCp Cp22Zr(H)Cl.
Zr(H)Cl.
2.2.4.
2.2.4. Beaundry’s
Beaundry’s Research
Research
During
During their research,Beaundry’s
their research, Beaundry’sgroup
groupproposed
proposed the the
formal synthesis
formal of lysergic
synthesis acid
of lysergic
via the Hendrickson intermediate as an example of using this method for
acid via the Hendrickson intermediate as an example of using this method for the prepa-the preparation
of substituted
ration indolesindoles
of substituted [68]. The synthesis
[68]. relies onrelies
The synthesis the coupling of a terminal
on the coupling alkyne alcohol
of a terminal alkyne
and a halogen derivative of the pyridine ester 76 and the substitution of an
alcohol and a halogen derivative of the pyridine ester 76 and the substitution of an amine amine with
awith
cyclic substituent,
a cyclic followed
substituent, by the by
followed closure of the indole
the closure of the system, leading leading
indole system, to the known
to the
precursor 65, from which the Hendrickson’s intermediate can be obtained in two steps.
known precursor 65, from which the Hendrickson’s intermediate can be obtained in two
steps.
Chloropyridine 76 was prepared according to the procedure in the literature [64]. The
Sonogashira coupling of the alkyne and chloropyridine was performed using microwave
heating. Compound 77 was then activated with triflate anhydride and converted to a sec-
During their research, Beaundry’s group proposed the formal synthesis of lysergic
acid via the Hendrickson intermediate as an example of using this method for the prepa-
ration of substituted indoles [68]. The synthesis relies on the coupling of a terminal alkyne
alcohol and a halogen derivative of the pyridine ester 76 and the substitution of an amine
Molecules 2022, 27, 7322 with a cyclic substituent, followed by the closure of the indole system, leading 21 toofthe
56
known precursor 65, from which the Hendrickson’s intermediate can be obtained in two
steps.
Chloropyridine76
Chloropyridine 76was
was prepared
preparedaccording
accordingto
tothe
theprocedure
procedurein
inthe
the literature
literature[64].
[64]. The
The
Sonogashira
Sonogashira coupling
coupling of of the
the alkyne
alkyne and
and chloropyridine
chloropyridine was
was performed
performed using
using microwave
microwave
heating. Compound77
heating. Compound wasthen
77was thenactivated
activated with
with triflate
triflate anhydride
anhydride andand converted
converted to a to a
sec-
secondary amine
ondary amine 78 78 (Scheme
(Scheme 30).30).
Scheme 30.
Scheme 30. Beginning
Beginning of
of the
the synthesis
synthesis proposed
proposed by
by Beaundry.
Beaundry.
The
The research
research of
of the
the Beaundry
Beaundry group
group focused
focused on
on the
the preparation
preparation of
of the
the bicyclic
bicyclic system
system
of
of substituted
substituted indole, and, as a result, the methods of oxidative cyclization were opti-
mized:
mized: in the first step, butyl nitrile was added under basic conditions and stronglystrongly heated
heated
with
with microwave, and then HO-TEMPO was added in the presence of copper (I) salt and
microwave, and then HO-TEMPO was added in the presence of copper (I) salt and
controlled
controlled amounts
amounts of of oxygen
oxygen to
to give
give the
the indolyl-pyridine
indolyl-pyridine65 65in
ingood
goodyield.
yield.
Hendrickson’s
intermediate 67 67 can
can bebe obtained
obtained inin two
two steps,
steps, by
by the
the reduction
reduction and
and
cyclization
cyclization described
described above
above (Scheme
(Scheme 31)31) [64].
[64].
Scheme31.
Scheme 31. Ending
Endingof
ofthe
thesynthesis
synthesisproposed
proposedby
byBeaundry.
Beaundry.
2.3.
2.3. Szantay’s
Szantay’sStrategy
Strategy
2.3.1. Direct Szantay’s Research
2.3.1. Direct Szantay’s Research
Szantay proposed the synthesis of lysergic acid using an aldol condensation reaction
Szantay proposed the synthesis of lysergic acid using an aldol condensation reaction
to close the D ring. The first presentation of the synthesis of (+)-lysergic acid is also a great
to close the D ring. The first presentation of the synthesis of (+)-lysergic acid is also a great
achievement, thanks to the use of the obtained tetracyclic system, which was separated by
achievement, thanks to the use of the obtained tetracyclic system, which was separated by
crystallization with a chiral auxiliary. In doing so, he obtained a key intermediate (R)-82
crystallization with a chiral auxiliary. In doing so, he obtained a key intermediate (R)-82
(Szantay’s intermediate). The next four steps are required to obtain lysergic acid. The
(Szantay’s intermediate). The next four steps are required to obtain lysergic acid. The ar-
article also describes, in addition to the lysergic acid total synthesis, the synthesis of an
ticle also describes,
important derivativeinofaddition to the lysergic
ergocriptinine, which is acid total synthesis,
a peptide derivativetheofsynthesis of anon
lysergic acid im-
a
portant derivative
large scale [70]. of ergocriptinine, which is a peptide derivative of lysergic acid on a
largeThe
scale [70].
synthesis involved going through the following steps: obtaining a tricyclic ke-
tone, The synthesis
closing involved
the fourth going the
ring using through
aldol the following
reaction, steps: obtaining
enantioselective a tricyclic
separation ke-
of the
tone, closing
obtained the fourth
product, ring using the
and substituting the aldol
carbonylreaction,
groupenantioselective
with a carboxylic separation of the
acid to obtain
obtained product,
(+)-lysergic acid. and substituting the carbonyl group with a carboxylic acid to obtain
(+)-lysergic acid. was started with the preparation of the bromo derivative of Uhle’s
The synthesis
The synthesis
ketone 79. The original was procedure
started with forthethepreparation
preparation ofof
the bromo
Uhle’s derivative
ketone of Uhle’s
assumed ke-
starting
tone 79. The original procedure for the preparation of Uhle’s ketone
from the 3-indolpropionic acid 6 by the Goto method [71]; however, only the preparation assumed starting
from
of the the 3-indolpropionic
bromo derivative made acidit 6possible
by the Goto method
to carry [71];
out the however,reaction.
amination only theThe
preparation
authors
of the bromo
proposed derivative
two methods ofmade it possible
obtaining compound to carry out the
80 from the amination reaction.
bromo derivative 79The authors
(Scheme 32
proposed two methods of obtaining compound 80 from the bromo derivative
shows a two-step synthesis with a yield of 35%, but an alternative is a four-step process 79 (Scheme
32 shows
with a totala yield
two-step
thatsynthesis
is higher with
by 4%).a yield
Next,ofthe
35%, NHbut an alternative
group is a four-step
of the indole process
was deprotected.
with a total yield that is higher by 4%). Next, the NH group of the indole was deprotected.
The synthesis was started with the preparation of the bromo derivative of Uhle’s ke-
tone 79. The original procedure for the preparation of Uhle’s ketone assumed starting
from the 3-indolpropionic acid 6 by the Goto method [71]; however, only the preparation
of the bromo derivative made it possible to carry out the amination reaction. The authors
proposed two methods of obtaining compound 80 from the bromo derivative 79 (Scheme
Molecules 2022, 27, 7322 22 of 56
32 shows a two-step synthesis with a yield of 35%, but an alternative is a four-step process
with a total yield that is higher by 4%). Next, the NH group of the indole was deprotected.
Scheme32.
Beginningof
ofthe
thesynthesis
synthesisproposed
proposedby
bySzantay.
Szantay.
The
The next step involved
involvedclosing
closingthe theDDring.
ring.ForFor
thisthis purpose,
purpose, intramolecular
intramolecular aldolaldol
con-
condensation was employed, using 1,5-dicarbonyl moiety 81, formed
densation was employed, using 1,5-dicarbonyl moiety 81, formed after the deprotection after the deprotection
of
ofketone
ketone80. 80. However,
However,selecting
selectingthe theoptimal
optimalconditions
conditionswas wasaadifficult
difficulttask.
task.Bases
Bases ranging
ranging
from
from tert-butoxide to bases such as LiHMDS were tested with no effect. A satisfactory
tert-butoxide to bases such as LiHMDS were tested with no effect. A satisfactory
effect
effectwas
wasachieved
achievedusing
usingthe
theEschenmoser
Eschenmoserconditions—LiBr
conditions—LiBrand andtriethylamine
triethylamine[72]. [72].
The
The authors suggest that
authors suggest that the
thetetracyclic
tetracyclicproduct
product8282is is formed
formed byby lithium
lithium bromide
bromide ac-
activation of the carbonyl groups in the presence of an amine, due to
tivation of the carbonyl groups in the presence of an amine, due to the higher affinity of the higher affinity
Molecules
Molecules 2022,
2022, 27,
27, xx FOR
FOR PEER
PEER REVIEW
REVIEW
of lithium 23
23 of
of 56
56
lithium forforoxygen
oxygenthanthannitrogen.
nitrogen.The Thepresence
presenceofofthe the amine
amine isis essential—it
essential—it is is used
used to to
abstract
abstractaaproton
protonfromfromthe
thealpha
alphaposition
positionnext
nexttotothe
thecarbonyl
carbonyl group.
group.These
These initial
initialsynthesis
synthe-
steps make use of the synthesis intermediates already proposed by
sis steps make use of the synthesis intermediates already proposed by Woodward [31]. Woodward [31].
The
The best
The best effect
effect was
best effect was achieved
was achieved
achieved by by performing
by performing
performing the the deprotection
the deprotection
deprotection andand cyclization
and cyclization reaction
reaction
without
without isolating
without isolating compound
isolating compound
compound 8181 and
81 and isolating
and isolating compound
isolating compound
compound 8282 by crystallization
82 by to
by crystallization give
crystallization to agive
totalaa
to give
60%
totalyield
total 60% of these
60% yield
yield of steps steps
of these
these (Scheme
steps 33). 33).
(Scheme
(Scheme 33).

Scheme 33. Preparation of
of the
the carbonyl α,β-unsaturated system
carbonylα,β-unsaturated system 82.
82.
Enantioselective
Enantioselectiveseparation
Enantioselective separationwas
separation was
wasperformed
performed
performed byby
crystallization
by with
crystallization
crystallization chiral
with
with dibenzoyltar-
chiral
chiral dibenzo-
dibenzo-
taric acid,acid,
yltartaric
yltartaric and pure
acid, and compound
and pure
pure compound
compound was obtained,
(R)-82(R)-82
(R)-82 was contributing
was obtained,
obtained, to theto
contributing
contributing first
to theasymmetric
the first
first asym-
asym-
synthesis
metric of (+)-lysergic
metric synthesis
synthesis of acid. The
of (+)-lysergic
(+)-lysergic physicochemical
acid.
acid. The properties
The physicochemical
physicochemical of the of
properties
properties obtained
of the compound
the obtained
obtained com-
com-
were
pound compared with the degradation product of natural (+)-lysergic acid.
pound were compared with the degradation product of natural (+)-lysergic acid. The op-
were compared with the degradation product of natural (+)-lysergic The
acid. optically
The op-
pure
ticallyisomer
tically pure (R)-82—Szantay’s
pure isomer
isomer intermediate—was
(R)-82—Szantay’s
(R)-82—Szantay’s intermediate—was
intermediate—wasreactedreacted
with isonitrile
reacted with to produce
with isonitrile
isonitrile to a
to pro-
pro-
tosylated
duce formamide
duce aa tosylated derivative
tosylated formamide 83
formamide derivative (Scheme
derivative 83 34).
83 (Scheme
(Scheme 34).
34).
Scheme 34.
Scheme 34.
Scheme Obtaining
34. Obtaining Szantay’s
Obtaining Szantay’s intermediate.
Szantay’s intermediate.
intermediate.
Basic
Basic hydrolysis
hydrolysis gave
gave the
the R/S
R/S nitrile
nitrile mixture
mixture (84),
(84), which
which was
was converted
converted to
to the
the R/S
R/S
methyl ester mixture 51 by Pinner reaction. Basic ester hydrolysis gave pure (+)-lysergic
methyl ester mixture 51 by Pinner reaction. Basic ester hydrolysis gave pure (+)-lysergic
acid
acid by
by epimerization
epimerization (Scheme
(Scheme 35)
35) [70].
[70].
Molecules 2022, 27, 7322 23 of 56
Scheme 34. Obtaining Szantay’s intermediate.
Basic
Basic hydrolysis
hydrolysis gave
gavethe
theR/S
R/S nitrile
nitrile mixture
mixture (84),
(84),which
whichwas
wasconverted
convertedtotothe
theR/S
R/S
methyl
methyl ester
ester mixture 51by
mixture51 byPinner
Pinnerreaction.
reaction.Basic
Basicester
esterhydrolysis
hydrolysisgave
gavepure
pure(+)-lysergic
(+)-lysergic
acid
acidby
byepimerization
epimerization(Scheme
(Scheme35)
35)[70].
[70].
Scheme35.
Scheme 35. Synthesis
Synthesisof
oflysergic
lysergicacid
acidproposed
proposedby
bySzantay.
Szantay.
2.3.2.
2.3.2. Continuation
Continuation of of Szantay’s
Szantay’sResearch
Research
AA year later, in 2005, HelveticaChimica
year later, in 2005, Helvetica ChimicaActa
Actapublished
publishedaareview
reviewpresenting
presenting the
the entire
entire
range of works by Szantay’s group [73]. Unfortunately, the only successful
range of works by Szantay’s group [73]. Unfortunately, the only successful attempt to ob- attempt to
obtain lysergic acid was the synthesis presented in Section 2.3.1, although the work
tain lysergic acid was the synthesis presented in Section 2.3.1, although the work resulted resulted
in
inaanumber
numberofofinteresting
interestingfour- and
four- five-cyclic
and compounds
five-cyclic compounds based
basedon the ergoline
on the structure,
ergoline struc-
obtained by Stobbe
ture, obtained (Figure
by Stobbe 12). 12).
(Figure

Figure 12. Structural formulas
formulas of
of compounds
compounds obtained
obtained in
in further
further works
works of
of Szantay’s
Szantay’s research
research group.
group.
2.3.3.
2.3.3. Garner’s
Garner’s Research
Research
In 2021, Garner and Rathnayake published a study that used Szantay’s intermediate
In 2021, Garner and Rathnayake published a study that used Szantay’s intermediate
to obtain lysergic acid [74]. This is a novel approach that involves carrying out an
to obtain lysergic acid [74]. This is a novel approach that involves carrying out an intra-
intramolecular cycloaddition reaction of an azomethine ylide, generated in situ, followed
molecular cycloaddition reaction of an azomethine ylide, generated in situ, followed by
by ring expansion to Szantay’s ketone. During these reactions, C and D’ rings (where D’
ring expansion to Szantay’s ketone. During these reactions, C and D’ rings (where D’ is a
is a five-membered precursor of the D ring in the ergoline structure) are obtained, and
five-membered precursor of the D ring in the ergoline structure) are obtained, and then
then they are transformed into CD rings. The disadvantage of this method is a very large
they are transformed into CD rings. The disadvantage of this method is a very large num-
number of stages—Szantay’s intermediate (R)-82 is obtained in 16 stages, with a total yield
ber of stages—Szantay’s intermediate (R)-82 is obtained in 16 stages, with a total yield of
of 1.0% (average—75% per step).
1.0% (average—75% per step).
The synthesis was started with 4-bromoindole 61, which was converted into the bro-
moindole 88 derivative, according to a procedure in the literature [75]. Then, using a
moindole 88 derivative, according to a procedure in the literature [75]. Then, using a So-
Sonogashira coupling and removal of the TMS group, terminal acetylene 89 was obtained,
nogashira
which was coupling andwith
substituted removal of the TMS
the sulfonyl group,
group. Theterminal
obtainedacetylene
compound 89 90
was obtained,
was depro-
which was substituted with the sulfonyl group. The obtained compound 90 was
tected to the form of an alcohol and oxidized to aldehyde 91, which was a substrate fordepro-
the
tected to the form
intramolecular of an alcohol
cycloaddition and oxidized
reaction (Scheme to
36).aldehyde 91, which was a substrate for
the intramolecular cycloaddition reaction (Scheme 36).
1.0% (average—75% per step).
moindole 88 derivative, according to a procedure in the literature [75]. Then, using a So-
nogashira coupling and removal of the TMS group, terminal acetylene 89 was obtained,
which was substituted with the sulfonyl group. The obtained compound 90 was depro-
Molecules 2022, 27, 7322 24 of 56
tected to the form of an alcohol and oxidized to aldehyde 91, which was a substrate for
the intramolecular cycloaddition reaction (Scheme 36).
Scheme36.
Scheme 36.Beginning
Beginningof
ofthe
thesynthesis
synthesisproposed
proposedby
byGarner.
Garner.
The
Thesecond
secondsubstrate
substratewaswascompound
compound93, 93,aachiral
chiralglycylsultam,
glycylsultam,obtained
obtainedin inaa five-step
five-step
synthesis
synthesisfromfrom(2S)-bornane-2,10-sultam
(2S)-bornane-2,10-sultam a camphor
92,92, a camphor derivative. The
derivative. The steps of substituting
steps of substitut-
the
ingacid
the halide with an
acid halide withorganolithium agent agent
an organolithium were performed, followed
were performed, by the introduction
followed by the intro-
of the -NH2 group by the azide. The intramolecular cycloaddition of an
duction of the -NH2 group by the azide. The intramolecular cycloaddition of an azome-azomethine ylide
isthine
an asymmetric cycloaddition reaction of three elements: aldehyde, dipolarophilic
ylide is an asymmetric cycloaddition reaction of three elements: aldehyde, dipolar- factor
(in this case
ophilic in (in
factor onethis
substrate oneand
case in91), glycylsultane.
substrate As a result ofAs
91), and glycylsultane. the reaction—as
a result the
of the reac-
authors suggest—through the intermediate 94, a system of four ABCD rings is 25 of 56
formed
tion—as the authors suggest—through the intermediate 94, a system of four ABCD rings
(Scheme
is formed 37) in an enantioselective
(Scheme reaction. reaction.
37) in an enantioselective
Scheme37.
Preparationof
ofaatetracyclic
tetracyclicderivative
derivative95
95with
withaacamphor
camphorsubstituent.
substituent.
In
Inthe
thefollowing
followingsteps,
steps,aafragment
fragmentofofthe
thecamphor
camphor derivative
derivativewas wasremoved,
removed,and thethe
and D
ring substituent was reduced, yielding alcohol 97. Then, using the five- to six-membered
D ring substituent was reduced, yielding alcohol 97. Then, using the five- to six-membered
ring
ring expansion
expansion reaction
reaction proposed
proposed by by Cossy
Cossy andand Charette
Charette [76,77],
[76,77], the
the correct
correct system
system was
was
obtained 98.
obtained 98.
The
The oxidation and deprotection
oxidation and deprotectionof ofcompound
compound9999allowed
allowed forfor obtaining
obtaining Szantay’s
Szantay’s in-
intermediate fromwhich
(R)-82,from
termediate (R)-82, whichthetheproper,
proper, optically
optically pure
pure (+)-lysergic
(+)-lysergic acid
acid can
can be
be obtained
obtained
in
infour
foursteps
steps(Scheme
(Scheme38).
38).
In the following steps, a fragment of the camphor derivative was removed, and the
D ring substituent was reduced, yielding alcohol 97. Then, using the five- to six-membered
ring expansion reaction proposed by Cossy and Charette [76,77], the correct system was
obtained 98.
The oxidation and deprotection of compound 99 allowed for obtaining Szantay’s in-
Molecules 2022, 27, 7322 25 of 56
termediate (R)-82, from which the proper, optically pure (+)-lysergic acid can be obtained
in four steps (Scheme 38).
Scheme38.
Scheme 38.Synthesis
Synthesisof
oflysergic
lysergicacid
acidproposed
proposedby
byGarner.
Garner.
2.4.
2.4.Closing
Closingthe
theC/D-Ring
C/D-RingUsing
Usingthe
theHeck
HeckMethod
Method
The
The Mizoroki–Heck reaction, includingthe
Mizoroki–Heck reaction, including theintramolecular
intramolecularversion,
version,isisthe
thereaction
reactionofof
the
theselective
selectivecoupling
couplingofof
ananaryl or or
aryl vinyl halide
vinyl halideandand
an alkene in the
an alkene in presence of a palladium
the presence of a palla-
catalyst under under
dium catalyst basic conditions [78]. It[78].
basic conditions is often used to
It is often enclose
used the six-membered
to enclose the six-memberedC-ring
C-
in the ergoline structure. A lot of synthetic work was based on the scheme: preparation
of halogen-indole or tryptophan derivatives, then coupling of the D-ring, manipulation
of substituents to create favorable conditions for the intramolecular Heck reaction, and
conversion of the functional groups to (+)-lysergic acid.
2.4.1. Ortar and Kurihara Groups

Strategy of closing D-ring using the Heck method. In 1988, the Ortar group was the
first to propose the preparation of lysergic acid through the palladium-catalyzed Heck
coupling [79]. The starting material in the synthesis was Uhle’s ketone derivative 5 [31].
The tricyclic olefin 100 was obtained, as a substrate for the coupling reaction, after the
use of a pyridine derivative and triflic anhydride. The second substrate was the unsaturated
amino ester 102, which was obtained by carbanion generation from amino ester 101, the
addition of formaldehyde, the introduction of mesyl chloride, and elimination promoted
by strong base DBU.
Heck coupling resulted in compound 103, which readily cyclizes in the presence of
hydrochloric acid (Scheme 39).
The tricyclic olefin 100 was obtained, as a substrate for the coupling reaction, after
the use of a pyridine derivative and triflic anhydride. The second substrate was the un-
saturated amino ester 102, which was obtained by carbanion generation from amino ester
101, the addition of formaldehyde, the introduction of mesyl chloride, and elimination
promoted by strong base DBU.
Molecules 2022, 27, 7322 26 of 56
Heck coupling resulted in compound 103, which readily cyclizes in the presence of
hydrochloric acid (Scheme 39).
Scheme 39.
Scheme39.
Scheme Preparation
39.Preparation of
ofaaatricyclic
Preparationof tricyclic system
tricyclicsystem by
systemby Heck
byHeck coupling
Heckcoupling as
couplingas the
asthe source
thesource of
sourceof the
ofthe D-ring.
theD-ring.
D-ring.
AA mixture of the
mixture of thetwo
twoepimers
epimers3131was
was obtained
obtained with
with a yield
a yield of 60%,
of 60%, in a ratio
in a ratio of
of 1.7:1.
1.7:1. Despite
Despite being being consistent
consistent with
with the the spectral
spectral data reported
data reported by Ninomiya
by Ninomiya and Rebek,
and Rebek, reflux-
refluxing the mixture
ing the ester ester mixture 31 in methanol
31 in methanol did
did not not result
result inratio,
in a 3:1 a 3:1 as
ratio, as reported
reported in the in the
litera-
literature [54,58].
ture [54,58]. Nevertheless,
Nevertheless, using
using the obtained
the obtained mixture
mixture of esters,
of esters, thethe target
target product
product cancan
be
be prepared, which ends the formal synthesis of lysergic acid (Scheme
prepared, which ends the formal synthesis of lysergic acid (Scheme 40) [31,32].40) [31,32].
Scheme 40.
Scheme40.
Scheme Synthesis
40.Synthesis of
Synthesisof lysergic
oflysergic acid
lysergicacid ester
acidester 51
ester51 proposed
51proposed by
proposedby Ortar.
byOrtar.
Ortar.
Kurihara group
Kurihara group research.
research. Two
Two years
years earlier,
earlier,thetheKurihara
Kurihara group
group proposed
proposed aa method
method
of obtaining
of obtaining lysergic
lysergicacid
acid using
using the
the same
same substrates
substrates as as Ortar,
Ortar, reaching
reaching the
the same
same analogous
analogous
intermediate,
intermediate, which
which cancan be
be cyclized;
cyclized; however,
however, in in this
this case,
case, aa ring-closing
ring-closing reaction
reaction waswas
performed
performed without
without using
using the
the Heck
Heck coupling
coupling method
method [80,81].
[80,81]. The
The same
same intermediate
intermediate thatthat
was 27 of 56
wasalready
alreadydescribed
describedby byWoodward
Woodwardisisobtained
obtained[31].[31].
The
The substrate
substrate for
for the
the proposed
proposed synthesis
synthesis was
was thethe Uhle
Uhle ketone
ketone derivative
derivative 55 [31].
[31]. Con-
Con-
verting the carbonyl functional group first to nitrile and then to aldehyde
verting the carbonyl functional group first to nitrile and then to aldehyde via DIBAL-H via DIBAL-H
reduction
reductiongave gavecompound
compound22. 22.Then,
Then,using
usinga strong
a strong organolithium
organolithium base, LDA,
base, introduction
LDA, introduc-
was
tionperformed
was performedinto the
intotricyclic structure
the tricyclic of theofamine-ester
structure moiety.
the amine-ester moiety.
In
In the
the next
next stage,
stage, the
the alcohol
alcohol was
was changed
changed to to the
the -OMs
-OMs group,
group, obtaining
obtaining the
the mesylate
mesylate
104(Scheme
104 (Scheme41). 41).
Scheme 41.
Preparation of
of aa tricyclic
tricyclic system
systemby
byKurihara,
Kurihara,analogous
analogousto
tothat
thatof
ofOrtar.
Ortar.
Conversion into
Conversion into Woodward’s
Woodward’s key key intermediate
intermediate ethyl
ethyl ester
ester could
could be be carried
carried out
out in
in
two ways:
two ways: either
either 104
104 was
was deprotected
deprotected first
first and
and then
then cyclized,
cyclized, or
or itit was
was first
first treated
treated with
with
DBU, and,
DBU, and, in
in the
the next
next step,
step, the
the protecting
protecting group
group was
was removed.
removed. TheThe reaction
reaction runs
runs through
through
intermediate products, which was used by the Ortar group [79]. Three products were ob-
tained: a mixture of (R) and (S) of the expected N-benzoy1-2,3-dihydrolysergate and also
the double-bond isomerization product. Recrystallization of the mixture in ethyl acetate
allowed for the isolation of the pure product. The last step was hydrolysis and re-esterifi-
cation, leading to the known compound (R)-31, from which, according to the literature
Scheme 41. Preparation of a tricyclic system by Kurihara, analogous to that of Ortar.
Molecules 2022, 27, 7322 27 of 56

Conversion into Woodward’s key intermediate ethyl ester could be carried out in
two ways: either 104 was deprotected first and then cyclized, or it was first treated with
DBU, and, in the next step, the protecting group was removed. The reaction runs through
intermediate products, which
intermediate products, whichwas wasusedusedbybythe
theOrtar
Ortar group
group [79].
[79]. Three
Three products
products were were
ob-
obtained: a mixture
tained: a mixture of (R)
of (R) andand (S) (S) of the
of the expected
expected N-benzoy1-2,3-dihydrolysergate
N-benzoy1-2,3-dihydrolysergate and andalso
also the double-bond
the double-bond isomerization
isomerization product.
product. Recrystallization
Recrystallization of the mixture
of the mixture in ethylinacetate
ethyl
acetate allowed for the isolation of the pure product. The last step was hydrolysis
allowed for the isolation of the pure product. The last step was hydrolysis and re-esterifi- and
re-esterification, leading to the known compound (R)-31, from which,
cation, leading to the known compound (R)-31, from which, according to the literature according to the
literature [62], lysergic acid can be obtained
[62], lysergic acid can be obtained (Scheme 42). (Scheme 42).
Scheme 42.
Preparation of
of aa lysergic
lysergic acid
acid protected
protected ester
ester(R)-31
(R)-31by
bythe
theKurihara
Kuriharastrategy.
strategy.
2.4.2.
2.4.2. Fukuyama’s
Fukuyama’s Research
Research
Strategy I. In 2009,the
Strategy I. In 2009, theFukuyama
Fukuyamagroup
group proposed
proposed thethe synthesis
synthesis of (+)-lysergic
of (+)-lysergic acid
acid [80], which so far had only been possible through the Szantay approach [73].
[80], which so far had only been possible through the Szantay approach [73]. Lysergic acidLysergic
acid
was was prepared
prepared by closing
by closing the C-ring
the C-ring via
via an an intramolecular
intramolecular HeckHeck reaction
reaction usingusing the tri-
the tricyclic
cyclic compound 117. In turn, this compound could be obtained from the bromomagnesium
compound 117. In turn, this compound could be obtained from the bromomagnesium in-
indole derivative and from the disubstituted tetrahydropyridine. Chiral tetrahydropyri-
dole derivative and from the disubstituted tetrahydropyridine. Chiral tetrahydro-
dine, the structure of which corresponds to the D-ring, was obtained from L-pyroglutamic
pyridine, the structure of which corresponds to the D-ring, was obtained from L-pyroglu-
acid by a dissrotational electrocyclic reaction [82].
tamic acid by a dissrotational electrocyclic reaction [82].
The synthesis began with the acylation of lactam 108 and the reduction and dehydra-
The synthesis began with the acylation of lactam 108 and the reduction and dehydra-
tion of the hemiaminal to enamide 109. Using catalysis and two-phase conditions, alkene
tion of the hemiaminal to enamide 109. Using catalysis and two-phase conditions, 28
Molecules 2022, 27, x FOR PEER REVIEW alkene
of 56
was converted to dibromocyclopropane 110, which rearranged at high temperature into
was converted to dibromocyclopropane 110, which rearranged at high temperature into
carbocation 111 and then into the substituted dihydropyridine 112 (Scheme 43).
carbocation 111 and then into the substituted dihydropyridine 112 (Scheme 43).
Scheme43.
Synthesisof
ofdihydropyridine
dihydropyridine112.
112.
As
Asaaresult
resultofof
thethe
next seven
next stages
seven of the
stages ofsynthesis, a tetrahydropyridine
the synthesis, acid chloride
a tetrahydropyridine 115
acid chlo-
was prepared, which could be subsequently coupled to a tricyclic system using
ride 115 was prepared, which could be subsequently coupled to a tricyclic system using an organometal-
lic
ancompound. The resulting
organometallic compound.compound 112 was reduced
The resulting compound and then carbonylated
112 was reducedunder catalytic
and then car-
conditions. Using a Ritter’s method [83], the Cbz protecting group was replaced
bonylated under catalytic conditions. Using a Ritter’s method [83], the Cbz protecting with a -Ns
group
group(Scheme 44). Then,
was replaced with ait-Ns
wasgroup
possible to apply
(Scheme 44). the
Then,Jones oxidation
it was possiblewith chromium
to apply ox-
the Jones
ide, and thewith
oxidation compound
chromium obtained
oxide, in this
and theway was transformed
compound obtained into acid
in this chloride
way 115 by the
was transformed
Ghosez procedure [84]. Interestingly, this is the first example of the synthesis of
into acid chloride 115 by the Ghosez procedure [84]. Interestingly, this is the first exampleoptically pure
of the synthesis of optically pure dihydropyridine from L-pyroglutamic acid. As a result,
a chiral center is introduced into the compound, which makes it possible to obtain pure
(+)-lysergic acid.
As a result of the next seven stages of the synthesis, a tetrahydropyridine acid chlo-
ride 115 was prepared, which could be subsequently coupled to a tricyclic system using
ride 115 was prepared, which could be subsequently coupled to a tricyclic system using
an organometallic compound. The resulting compound 112 was reduced and then car-
an organometallic
bonylated compound.
under catalytic The resulting
conditions. Using compound 112 was[83],
a Ritter’s method reduced andprotecting
the Cbz then car-
bonylated under catalytic conditions. Using a Ritter’s method [83], the Cbz protecting
group was replaced with a -Ns group (Scheme 44). Then, it was possible to apply the Jones
group was replaced with a -Ns group (Scheme 44). Then, it was possible to apply the Jones
Molecules 2022, 27, 7322 oxidation with chromium oxide, and the compound obtained in this way was transformed 28 of 56
oxidation with chromium
into acid chloride oxide,
115 by the and the
Ghosez compound
procedure [84].obtained in thisthis
Interestingly, wayiswas transformed
the first example
into acid chloride 115 by the Ghosez procedure [84]. Interestingly, this is the first example
of the synthesis of optically pure dihydropyridine from L-pyroglutamic acid. As a result,
of the synthesis
a chiral center isofintroduced
optically pure
intodihydropyridine from L-pyroglutamic
the compound, which makes it possible acid.
to As a result,
obtain pure
dihydropyridine
a chiral center isfrom L-pyroglutamic
introduced into the acid. As a result,
compound, which a chiral
makes center is introduced
it possible intopure
to obtain the
(+)-lysergic acid.
compound,
(+)-lysergic which
acid. makes it possible to obtain pure (+)-lysergic acid.
Scheme 44. Protection of the tetrahydropyridine with a nosyl group.

Scheme 44.
Scheme 44. Protection
Protection of
of the
the tetrahydropyridine
tetrahydropyridine with
with aa nosyl
nosyl group.
group.
The coupling of the D-ring derived from piperidine 115 and the 4-bromoindole de-
couplingof
The was
coupling ofthe
theD-ring
D-ringderived
derivedfrom
from piperidine
piperidine 115 and thethe 4-bromoindole de-
rivative performed in moderate yield. The nitrogen115in and
the indole4-bromoindole
was protectedderiva-
with
rivative
tive was
Alloc, was
wherebyperformed
performed
the in in moderate
moderate
carbonyl yield.
yield.
group wasThe The nitrogen
nitrogen
activated in the
in reduced
and the indole indole
towas was protected
protected with
a diastereomeric with
Alloc,
mixture
Alloc, whereby
whereby the the carbonyl
carbonyl group group
was was activated
activated and and reduced
reduced to a to a diastereomeric
diastereomeric mixture
mixture of
of alcohol 117 (Scheme 45).
of alcohol
alcohol 117117 (Scheme
(Scheme 45).45).
Scheme45.
Scheme 45.Synthesis
Synthesisof
oftricyclic
tricyclicalcohol
alcohol117.
117.
Scheme 45. Synthesis of tricyclic alcohol 117.
Subsequent reactions involved the deprotection and methylation of tetrahydropyridine
nitrogen to give alcohol 118. Next, indole nitrogen was deprotected, and the alcohol
was reduced with triethylsilane under acidic conditions. The indole nitrogen was -Boc
protected, and the double bond was isomerized with 2,6-tert-butylphenol and lithium
tetramethylpiperide to give a mixture of diastereomeric esters 120 (Scheme 46).
These isomers were separated and subjected to an intramolecular Heck reaction closing
the C-ring of the ergoline structure to obtain the protected ester. The desired trans isomer
was obtained in excess (3:1). After deprotection of the indole nitrogen with trifluoroacetic
acid, ester 121 was obtained, which can be converted to lysergic acid (Scheme 47) [85].
Despite the undoubted advantage of the approach proposed by Fukuyama, which
allows for obtaining pure (+)-lysergic acid, there are many disadvantages associated with
it. First of all, the number of stages, since the procedure involves over 30 steps from the
starting lactam to the final product. Additionally, the use of a large number of protecting
groups should be mentioned as a consequence of the use of numerous organometallic
compounds, such as DIBAL-H, LTMP, or Grignard compounds, and other requirements
related to such active reagents, for example temperature control. Realizing the disadvan-
tages of the proposed approach, Fukuyama introduced numerous alterations in subsequent
publications.
Subsequent reactions involved the deprotection and methylation of tetrahydro-

pyridine nitrogen to give alcohol 118. Next, indole nitrogen was deprotected, and the al-
cohol was reduced with triethylsilane under acidic conditions. The indole nitrogen was -
Molecules 2022, 27, 7322 29 of 56
Boc protected, and the double bond was isomerized with 2,6-tert-butylphenol and lithium
Scheme 46. Preparation of ester 120.
These isomers were separated and subjected to an intramolecular Heck reaction clos-
ing the C-ring of the ergoline structure to obtain the protected ester. The desired trans
isomer was obtained in excess (3:1). After deprotection of the indole nitrogen with tri-
fluoroacetic acid, ester 121 was obtained, which can be converted to lysergic acid (Scheme
Scheme
47) 46.Preparation
[85].46.
Scheme Preparationof
ofester
ester120.
120.
These isomers were separated and subjected to an intramolecular Heck reaction clos-
ing the C-ring of the ergoline structure to obtain the protected ester. The desired trans
isomer was obtained in excess (3:1). After deprotection of the indole nitrogen with tri-
fluoroacetic acid, ester 121 was obtained, which can be converted to lysergic acid (Scheme
47) [85].
Scheme 47.
Preparation of
of lysergic
lysergicacid
acidin
inFukuyama
Fukuyamastrategy
strategyI.I.
Strategy
Despite the II. The Fukuyama
undoubted group continued
advantage to workproposed
of the approach on new methods
by Fukuyama,of obtaining
which
lysergic
allows acid.
for The
obtaining aim was
pure to simplify
(+)-lysergic and
acid, shorten
there are the synthesis
many and
disadvantagesincrease the overall
associated
Molecules 2022, 27, x FOR PEER REVIEW 30 with
of 56
yield. A of
it. First synthesis
all, the based
number onof a one-pot
stages, sincedouble-cyclization
the procedurereaction,
involvessimultaneously
over 30 steps from closing
the
the B andlactam
starting C rings, thanks
to the finaltoproduct.
an intramolecular
Additionally, amination
the use reaction
of a largetonumber
the aromatic system
of protecting
(to the indole
Scheme
groups ABbesystem)
47. Preparation
should and the
of lysergic
mentioned apalladium-catalyzed
asacid of theHeck
in Fukuyama strategy
consequence I. of
use reaction
numerous(ringorganometallic
C), have been
proposed
proposed [86].
[86]. In
In order
order to
to obtain
obtain the substrate for the double-cyclization
compounds, such as DIBAL-H, LTMP, or Grignard compounds, and other requirements reaction, the syn-
thesis
thesis
related ofto
of compound
compound
Despite suchtheactive 131reagents,
131
undoubted was carried
was carried
advantage out
forout by
by the
of the
example coupling
thecoupling method
approachmethod
temperature proposed of dibromo-iodobenzene
of
control. dibromo-iodobenzene
by Fukuyama,
Realizing which
the disad-
and
and
allowsnitrated
for olefin
obtaining 127.
127.
pure The synthesis
(+)-lysergic uses
acid, 2-(but-3-en-1-yl)-propane-1,3-diole
vantages of the proposed approach, Fukuyama introduced numerous alterations in as
nitrated olefin The synthesis uses 2-(but-3-en-1-yl)-propane-1,3-diole
there are many disadvantages 122
associated as aa
with
sub-
starting
starting material.
material.
it. First of
sequent all, the number of stages, since the procedure involves over 30 steps from the
publications.
The
The
starting synthesis
synthesis
lactam
Strategy of the
of
II.toThe
the the optically
optically
final
Fukuyamaproduct. active
active
group nitroolefinthe
nitroolefin
Additionally,
continued 127
to127 was
was
use
work started
started
ofona large with
with
number
new methods lipase-mediated
lipase-mediated
of
of protecting
obtaining
acetylation
acetylation
groups and
and
should conversion
conversion
be mentioned of
of the
the
as second
second
a -OH
consequence group
of to
the the
use amide
of
lysergic acid. The aim was to simplify and shorten the synthesis and increase the overall under
numerous Mitsunobu con-
organometallic
ditions,
ditions,
compounds,
yield. achieving
Aachieving an
an
such based
synthesis optically
as optically
DIBAL-H, pure
pure
on a one-potLTMP, product
product (95% ee)
(95%
or Grignard
double-cyclization ee) and
and preventing
preventing
compounds,
reaction, and racemization.
racemization.
other
simultaneously The
The
requirements
closing
cyclic
cyclic
relatedacetate
acetate
to 124
124
such was
was
active then
then obtained
obtained
reagents, for after
after dehydration
dehydration
example of
temperatureofthe
the hemiaminal
hemiaminal
control.
the B and C rings, thanks to an intramolecular amination reaction to the aromatic system (Scheme
(Scheme
Realizing the 48).
48).
disad-
vantages
(to of the
the indole ABproposed approach,
system) and Fukuyama introduced
the palladium-catalyzed Hecknumerous alterations
reaction (ring inbeen
C), have sub-
sequent publications.
Strategy II. The Fukuyama group continued to work on new methods of obtaining
lysergic acid. The aim was to simplify and shorten the synthesis and increase the overall
yield. A synthesis based on a one-pot double-cyclization reaction, simultaneously closing
the B and C rings, thanks to an intramolecular amination reaction to the aromatic system
(to the indole AB system) and the palladium-catalyzed Heck reaction (ring C), have been
Scheme 48.
Synthesis of
of cyclic
cyclic acetate-enamine
acetate-enamine 124.
124.
Acetate 124 was

Acetate 124 was converted
converted to
to the
the corresponding
corresponding p-nitrobenzoate
p-nitrobenzoateenamide 125, which
enamide125, which
was recrystallized from methanol.
was recrystallized from methanol. Enamide 125 was then treated with NIS in methanol,
in methanol,
followed
followedby bydehydrogenation
dehydrogenationwith
with DBU
DBUto to
give methoxy-olefin
give methoxy-olefin Stereoselective
126.126. attach-
Stereoselective at-
ment of theofside
tachment chainchain
the side was was
performed by treatment
performed withwith
by treatment allyltrimethylsilane (Scheme
allyltrimethylsilane 49).
(Scheme
49).
Scheme 48.
Synthesis of
of cyclic
cyclic acetate-enamine
acetate-enamine 124.
124.
Acetate 124
Acetate 124 was
was converted
converted to
to the
the corresponding
corresponding p-nitrobenzoate
p-nitrobenzoate enamide
enamide 125,
125, which
which
was recrystallized
was recrystallized from
from methanol.
methanol. Enamide
Enamide 125125 was
was then
then treated
treated with
with NIS
NIS in
in methanol,
methanol,
followed by
followed by dehydrogenation
dehydrogenation with
with DBUDBU to to give
give methoxy-olefin
methoxy-olefin 126.126. Stereoselective
Stereoselective at-
at-
Molecules 2022, 27, 7322 tachment of the side chain was performed by treatment with allyltrimethylsilane 30 of 56
(Scheme
tachment of the side chain was performed by treatment with allyltrimethylsilane (Scheme
49).
49).
Scheme 49.
Scheme 49. Introducing
Introducing an
an allylic
allylic system
system into
into molecule
molecule 126.
126.
After modifying
After modifying
After the protecting
modifying the protecting groups,
groups, nitroolefin
nitroolefin 127
127 was
127 was obtained
was obtained in two
obtained in two steps by
two steps by
reacting the
reacting the
reacting formed
the formed aldehyde
formed aldehyde with
aldehyde with nitromethane
with nitromethane (Scheme
nitromethane (Scheme 50).
(Scheme 50).
50).
Scheme 50.
Scheme
50. Preparation of
Preparation of nitroolefin
of nitroolefin 129.
nitroolefin 129.
129.
By using
By usingnitroolefin
nitroolefin129,
nitroolefin 129,the
129, thekey
the keycyclization
key cyclization
cyclization reactions
reactions
reactions leading
leading
leading to toto the
the the tetracyclic
tetracyclic
tetracyclic ergo-
ergo-
ergoline
line
line structure
structure
structure couldcould
could be performed.
be performed.
be performed. Synthesis
Synthesis
Synthesis was waswas continued
continued
continued with
withwith the formation
the formation
the formation of an or-
of anoforgano-
an or-
ganolithium
ganolithium
lithium compound
compound
compound from
fromfrom dibromoiodobenzene
dibromoiodobenzene
dibromoiodobenzene and coupling
and coupling
and coupling it withitit with
awith aa nitroolefin
nitroolefin
nitroolefin to form to
to
form
the
form thebicyclic
bicyclic
bicyclic
the compound
compound
compound 131. Then,
Then,
131.131. using
using
Then, the
thethe
using Heck
Heck
Heck couplingand
coupling
coupling and intramolecular31amine
andintramolecular
intramolecular of 56
amine
cyclization, two
cyclization, two new
new rings—B
rings—B and and C—were
C—wereformed,
formed,yielding
yieldingstructure
structure132
structure 132(Scheme
132 (Scheme51).
(Scheme 51).
51).
Scheme 51.
Scheme 51. Forming
Forming the
the B
B and C rings
and C rings in
in Fukuyama
Fukuyama strategy
strategy II.
II.
The next steps were the manipulation of the protecting groups to give the diester 134
and migration of the double bond from the C8–C9 position to the C9–C10 position using
DBU (Scheme 52) [87].
Finally, gradual deprotection of both Boc groups and the reductive methylation of
dehydropiperidine yielded lysergic acid methyl ester 51 as a mixture of diastereoisomers,
with spectroscopic data that were identical to those described in the literature [70]. This
compound can be converted into (+)-lysergic acid, according to the procedure proposed by
Szantay (Scheme 53) [70].
In conclusion, an asymmetric synthesis of the (+)-lysergic acid ester was achieved
using the Heck coupling reaction to close the C-ring of the ergoline structure. The chiral
center was introduced in the first step, thanks to the lipase reaction. Although compound 51
is obtained in a long sequence (analogous to the above work), the total yield is 1.25%, which
gives an average yield of 88% for a step.
Scheme 52. Preparation of a protected lysergic acid ester 135 by Fukuyama strategy II.
Scheme 51. Forming the B and C rings in Fukuyama strategy II.
The next steps were the manipulation of the protecting groups to give the diester 134
Molecules 2022, 27, 7322 31 of 56
Scheme 52. Preparation of a protected lysergic acid ester 135 by Fukuyama strategy II.
compound
Scheme
Scheme 52. can be converted
52. Preparation
Preparation of into (+)-lysergic
of aa protected
protected lysergic acid acid,
lysergic acid according
ester 135
ester 135 to thestrategy
by Fukuyama
by Fukuyama procedure
strategy II. proposed
II.
by Szantay (Scheme 53) [70].
compound can be converted into (+)-lysergic acid, according to the procedure proposed
by Szantay (Scheme 53) [70].
Scheme53.
Scheme 53. Deprotection
Deprotectionand
andmethylation
methylationof
oflysergic
lysergicacid
acidester
ester51.
51.
Molecules 2022, 27, x FOR PEER REVIEW Strategy III. Another

In conclusion, syntheticsynthesis
an asymmetric attempt to of obtain lysergic acid
the (+)-lysergic acidwas 32 ofby
esterundertaken
was achieved 56
Fukuyama’s
using the Heck team in 2013reaction
coupling [88]. The toacid
closecould be prepared
the C-ring from units
of the ergoline with stereogenic
structure. The chiral
centers in allylic
center was positions
introduced (136,
in the 137),
first followed
step, thanksby to athe
D-ring
lipaseclosing metathesis
reaction. Although reaction, and
compound
finally
Scheme a Heck
53.
51 is obtained
finally a Heck in reaction
Deprotection to
and
a long to
reaction close
sequencethe C-ring.
methylation of
close the(analogous Synthesis
lysergic acid
C-ring. Synthesis was
ester
to the above started
51. with
work), the
was started what is
withtotal
what known
yield in the
is 1.25%,
is known in
literature
which
the as
gives an
literature crotoylooxazolidinone
as average 138
yield of 88% for138
crotoylooxazolidinone (Scheme
a step. 54) [89].
(Scheme 54) [89].
In conclusion,
Strategy an asymmetric
III. Another synthetic synthesis
attempt of to the (+)-lysergic
obtain lysergic acid ester was achieved
was undertaken by
using the Heck
Fukuyama’s teamcoupling
in 2013reaction
[88]. The to close the C-ring
acid could of the ergoline
be prepared structure.
from units The chiral
with stereogenic
center
centerswas introduced
in allylic in the
positions first
(136, step,
137), thanks to
followed bythe lipaseclosing
a D-ring reaction. Althoughreaction,
metathesis compound and
51 is obtained in a long sequence (analogous to the above work), the total yield is 1.25%,
which gives an average yield of 88% for a step.
Strategy III. Another synthetic attempt to obtain lysergic acid was undertaken by
Fukuyama’s team in 2013 [88]. The acid could be prepared from units with stereogenic
centers in allylic positions (136, 137), followed by a D-ring closing metathesis reaction, and
Scheme 54.
Retrosynthetic analysis
analysis leading
leadingto
tosubstrates
substratesin
inFukuyama
Fukuyamastrategy
strategyIII.
III.
Compound138
Compound 138 was
was prepared,
prepared, which
which was
was in
in fact
fact an
an aldehyde
aldehyde masked
masked by
by oxazolidine.
oxazolidine.
An Evans aldol reaction was used to obtain an amide with a terminal olefin
An Evans aldol reaction was used to obtain an amide with a terminal olefin 139. 139. After
After
protection of the -OH groups with TBS, reduction of DIBAL-H was performed to
protection of the -OH groups with TBS, reduction of DIBAL-H was performed to give the give the
hemiaminal 136
hemiaminal 136 (Scheme
(Scheme55).
55).
Scheme 55. Preparation of the hemiaminal 136.

Scheme 54. Retrosynthetic analysis leading to substrates in Fukuyama strategy III.
Compound 138 was prepared, which was in fact an aldehyde masked by oxazolidine.
An Evans aldol reaction was used to obtain an amide with a terminal olefin 139. After
Molecules 2022, 27, 7322 32 ofthe
protection of the -OH groups with TBS, reduction of DIBAL-H was performed to give 56
hemiaminal 136 (Scheme 55).
Scheme 55.
Preparation of
of the
the hemiaminal
hemiaminal136.
136.
The
The preparation of ofthe
thesecond
secondstarting
starting material
material waswas carried
carried out out
usingusing the same
the same com-
compound
pound 138.138.TheThe EvansEvans reaction
reaction waswas performed
performed again—taking
again—taking advantage
advantage of fact
of the the fact
that
that
this this
aldolaldol reaction
reaction allows
allows stereochemical
stereochemical control
control at the
at the allylic
allylic position—using
position—using indole
indole al-
aldehyde, since
dehyde, since it it
is is known
known in in
thethe literature.
literature. Thereafter,
Thereafter, treatment
treatment withwith hydrazine
hydrazine gave gave
hy-
hydrazide
drazide 141, 141, which
which waswas converted
converted to the
to the acylacyl azide.
azide. CurtiusCurtius rearrangement
rearrangement of theofazide
the
azide under acidic conditions gave amine which, upon reduction with triethylsilane,
under acidic conditions gave amine which, upon reduction with triethylsilane, gave al- gave
allylamine
lylamine 142 (Scheme56).
142(Scheme 56).
Scheme 56.
Preparation of
of allylamine
allylamine 142.
142.
Having
Having both
both compounds—allylamine
compounds—allylamine142 142and
andthe
thehemiaminal 136—reductivealkyla-
hemiaminal136—reductive alkyl-
tion
ationwas
wasperformed.
performed.TheTheamine
aminewaswasthen
thenprotected
protectedwith
with-Boc,
-Boc,and
andthe
theDDring
ring was
was closed
closed
using ring-closingdouble-bond
using a ring-closing double-bondmetathesis
metathesisreaction.
reaction.TheThe second-generation
second-generation Grubbs
Grubbs cat-
catalyst was used in this reaction [90], which made it possible to perform cyclization
alyst was used in this reaction [90], which made it possible to perform cyclization to com- to
compound 144, with high efficiency (Scheme
pound 144, with high efficiency (Scheme 57). 57).
Scheme 57.
Scheme 57. Reaction
Reaction of
of allylamine
allylamine 142
142 and
and the
the hemiaminal
hemiaminal 136,
136, along
along with
with reduction
reduction by
by Grubbs
Grubbs
catalyst II.
catalyst II.
Closing the
Closing the D-ring
D-ring using
using the
the Heck
Heck method
method yielded
yielded tetracyclic
tetracyclic product
product 145,
145, with
with an
an
ergoline skeleton.
ergoline skeleton. Subsequently, the manipulation
Subsequently, the manipulation of
of protecting
protecting groups
groups and
and functional
functional
groups gave ester 51 and then (+)-lysergic acid, analogous to strategies I and II (Scheme
58). Two successive cyclization reactions were the key steps in this procedure.
Scheme 57. Reaction of allylamine 142 and the hemiaminal 136, along with reduction by Grubbs
catalyst II.
Molecules 2022, 27, 7322 33 of 56
Closing the D-ring using the Heck method yielded tetracyclic product 145, with an
ergoline skeleton. Subsequently, the manipulation of protecting groups and functional
groups
groups gave
gaveester 51and
ester51 andthen
then(+)-lysergic acid,
(+)-lysergic analogous
acid, analogousto strategies I and
to strategies II (Scheme
I and 58).
II (Scheme
Two successive
58). Two cyclization
successive reactions
cyclization werewere
reactions the key
thesteps in this
key steps inprocedure.
this procedure.
Scheme 58.
Scheme 58. Preparation of lysergic
lysergic acid
acid in
in Fukuyama
Fukuyama strategy
strategy III.
III.
IV. The
Strategy IV. The Fukuyama
Fukuyama team’steam’s recent
recent work
work deviates
deviates from the idea of usingusing thethe
Heck reaction and instead proposes the formation of a C–C bond between C10 and C11
by aziridine ring cleavage [91]. The reaction begins with the the preparation
preparation of of the
the substrate—
substrate—
an indoline derivative
derivative[92].[92].Studies
Studies have
have shown
shown thatthat indole
indole undergoes
undergoes sideside reactions
reactions as a
as a result of knitting the electron-rich 3 position in the bicyclic structure.
result of knitting the electron-rich 3 position in the bicyclic structure. The choice of the The choice
of the chiral
chiral substituent—(3R,
substituent—(3R, 5R, 10R)-trans-aziridine—allowed
5R, 10R)-trans-aziridine—allowed forperformance
for the the performanceof dia-of
diastereoselective reactions.
stereoselective reactions.
The
The synthesis
synthesisofofthetheallyl
allylindoline
indolinederivative started
derivative startedwith 2-bromophenylacetic
with 2-bromophenylacetic acidacid
148.
Installation of theofchiral
148. Installation auxiliary,
the chiral followed
auxiliary, by allylation
followed and reduction
by allylation of LiAlH
and reduction 4 , gave
of LiAlH 4,
the alcohol 149. The Mitsunobu reaction was then performed followed
gave the alcohol 149. The Mitsunobu reaction was then performed followed by deprotec- by deprotection
of theofBoc
tion the group. The closing
Boc group. The closingof the
offive-membered
the five-membered cyclecycle
of indoline 151 was
of indoline due34
151 was toofthe
due
56
to
amination
the aminationreaction in the
reaction in presence of copper
the presence saltssalts
of copper (Scheme 59). 59).
(Scheme
Scheme 59.
Beginning of
of the
the synthesis
synthesis according
according to
to Fukuyama
Fukuyama strategy
strategy IV.
IV.
Terminal olefin
olefin 151
151 was
was oxidized
oxidized to
to carboxylic
carboxylic acid 152 byby treatment
treatment with the Jones
reagent. The
reagent. The chiral
chiralbenzyloxazolidin-2-one
benzyloxazolidin-2-onewas wasreconnected,
reconnected,and
and a diastereoselective
a diastereoselective al-
aldol
dol reaction
reaction waswas performed
performed by reacting
by reacting acyloxazolidinone
acyloxazolidinone 153 153
and and an alkyne
an alkyne aldehyde
aldehyde in
in the
the presence
presence of a of a titanium
titanium chloride
chloride (Scheme
(Scheme 60). 60).
Scheme 59. Beginning of the synthesis according to Fukuyama strategy IV.
Terminal olefin 151 was oxidized to carboxylic acid 152 by treatment with the Jones
reagent. The chiral benzyloxazolidin-2-one was reconnected, and a diastereoselective al-
Molecules 2022, 27, 7322 34 of 56
dol reaction was performed by reacting acyloxazolidinone 153 and an alkyne aldehyde in
the presence of a titanium chloride (Scheme 60).
Scheme 60.
Preparation of
of alkyne
alkyne 154.
154.
The obtained
The obtained compound
compound 154 154 was
was converted
converted to to hydrazide
hydrazide using
using hydrazine
hydrazine and
and then
then
reacted
reactedwith
withnitrite.
nitrite.The
Theformed
formedacyl azide
acyl waswas
azide usedused
for Curtius rearrangement,
for Curtius analogous
rearrangement, to
analo-
the
goussequence of reactions
to the sequence ofdescribed
reactionsindescribed
the previous publication,
in the previousto give oxazolidinone
publication, 155 [88].
to give oxazoli-
The necessary
dinone stereogenic
155 [88]. centers
The necessary were, thus,centers
stereogenic incorporated into incorporated
were, thus, the compound. In the
into the com-
next
step,
pound.a nosyl group
In the next was
step,inserted
a nosyl in placewas
group of the oxazolidinone,
inserted which,
in place of upon the addition
the oxazolidinone, of
which,
lithium hydroxide, 35 of 56
upon the addition gave hydroxy-p-Ns-amide
of lithium hydroxide, gave156. The Mitsunobu reaction
hydroxy-p-Ns-amide followed,
156. The Mitsunobuand
trans-aziridine 157 was
reaction followed, and obtained (Scheme
trans-aziridine 15761).
was obtained (Scheme 61).
Upon treatment of aziridine 157 with Lewis acid, the three-membered ring was
cleaved stereospecifically. A tricyclic compound containing ABC rings of the ergoline sys-
tem was obtained. The structure 158 was introduced with an organotin substituent. Upon
its use, the D ring was closed by an intramolecular Mitsunobu reaction. The amine was
released from the -Ns protecting group with thioglycol acid, followed by methylation with
formalin and sodium cyanoborohydride, to give the tetracyclic compound 160 (Scheme
62).

Scheme 61. Synthesis of
of aziridine
aziridine 157
157 in the Mitsunobu
in the reaction.
Mitsunobu reaction.
Upon treatment of aziridine 157 with Lewis acid, the three-membered ring was cleaved
stereospecifically. A tricyclic compound containing ABC rings of the ergoline system was
obtained. The structure 158 was introduced with an organotin substituent. Upon its use,
the D ring was closed by an intramolecular Mitsunobu reaction. The amine was released
from the -Ns protecting group with thioglycol acid, followed by methylation with formalin
and sodium cyanoborohydride, to give the tetracyclic compound 160 (Scheme 62).
Molecules 2022, 27, 7322 35 of 56
Scheme 61. Synthesis of aziridine 157 in the Mitsunobu reaction.
Scheme 61. Synthesis of aziridine 157 in the Mitsunobu reaction.
Scheme 62. Closing the D-ring in Fukuyama strategy IV.

Scheme 62.
Scheme 62. Closing
Closing the
the D-ring
D-ring in
in Fukuyama
Fukuyama strategy
strategy IV.
IV.
After manipulation with protecting groups, indoline 160 was oxidized to indole with
After
After manipulation
manipulation with
with protecting
protecting groups,
groups, indoline 160 was
indoline 160 was oxidized
oxidized to to indole
indole with
with
(PhSeO)
(PhSeO) 2O. The organotin substituent was replaced with an alkenyl iodide, followed by
(PhSeO)2O. The organotin substituent was replaced with an alkenyl iodide, followedthe
2 O. The organotin substituent was replaced with an alkenyl iodide, followed by by
the incorporation
incorporation of COof carbon
CO carbon monoxide
monoxide in theinpresence
the presence of palladium,
of palladium, to obtain
to obtain an epi-
an epimeric
the incorporation of CO carbon monoxide in the presence of palladium, to obtain an epi-
meric mixture
mixture of esters
of esters 162. 162.
TheseThese esters
esters cancanbe be converted
converted to to lysergicacid
lysergic acid bythethe methods
meric mixture of esters 162. These esters can be converted to lysergic acidby by the methods
methods
presented
presented in the previous publications by the Fukuyama group or by the method pro-
presentedininthe
theprevious
previous publications
publicationsbybythethe
Fukuyama
Fukuyama group or byorthe
group bymethod proposed
the method pro-
posed
in in this publication
this publication by treatment
by treatment with
with TFA, TFA, decarboxylation
decarboxylation by heatingby with
heating with pyri-
pyridine, and
posed in this publication by treatment with TFA, decarboxylation by heating with pyri-
dine, and
alkaline alkaline hydrolysis
hydrolysis (Scheme (Scheme 63).
63).
dine, and alkaline hydrolysis (Scheme 63).
Scheme 63.
Scheme 63. Preparation of lysergic
lysergic acid
acid in
in Fukuyama
Fukuyama strategy
strategy IV.
IV.
Scheme 63. Preparation of lysergic acid in Fukuyama strategy IV.
Many years of research by the Fukuyama group have led to a number of solutions
to the problem of total synthesis of (+)-lysergic acid. All methods are complex syntheses,
focused on the gradual preparation of substrates for the C-ring closure reaction, usually
the Heck reaction.
2.4.3. Liu and Jia Research

Strategy I. The work of Liu and Jia, from 2011, shows a method of obtaining (+)-
lysergic acid in which the starting material is the (R)-derivative of indole 164, as a result
of the D ring closing reaction in the double-bond metathesis reaction, followed by the
intramolecular Heck reaction [93]. This is a very similar procedure to the one proposed by
Fukuyama, but much shorter [86]. The starting indole derivative can be obtained using
D-glutamic acid 163 [92].
The synthesis begins with the methylation of the amine with methyl iodide, followed
by reduction with borohydride and Swern oxidation. The obtained aldehyde 166 can be
used for the Wittig reaction (Scheme 64).
of the D ring closing reaction in the double-bond metathesis reaction, followed by the
intramolecular Heck reaction [93]. This is a very similar procedure to the one proposed by
Fukuyama, but much shorter [86]. The starting indole derivative can be obtained using D-
glutamic acid 163 [92].
The synthesis begins with the methylation of the amine with methyl iodide, followed
Molecules 2022, 27, 7322 36 of 56
by reduction with borohydride and Swern oxidation. The obtained aldehyde 166 can be
used for the Wittig reaction (Scheme 64).
Scheme 64.
Beginning of
of the
the synthesis
synthesis of
of lysergic
lysergicacid
acidfrom
fromD-glutamic
D-glutamicacid
acid163.
163.
Enol
Enol ether 167 was
ether 167 was obtained
obtained by
bytreatment
treatmentwith
withmethoxymethylene
methoxymethyleneylide.
ylide. Successive
Successive
reactions
reactionsgave
gavediene 169,which
diene169, whichwas
was aa substrate
substrate for
for the
the D-ring
D-ring and
and then
then C-ring
C-ring cyclization
cyclization
reaction
reaction (Scheme
(Scheme65).
65).
Scheme 65.
Introducing of
of two
two terminal
terminal double
doublebonds
bondsinto
intomolecule
molecule166
166in
instrategy
strategyI.I.
Compound 169 was treated with a second-generation Grubbs catalyst in the presence
of p-TsOH acid [90]. It was tested that, in addition to the presence of a Lewis acid, the
choice of solvent (toluene) played a crucial role in the success of the reaction.
Following the synthesis of tricyclic 170, various C-ring closing pathways were in-
vestigated. The γ arylation reaction was unsuccessful, so the Heck reaction was tested.
After finding the optimized conditions, the reaction was performed in the presence of two
equivalents of silver carbonate in hot MeCN to give compound 171 (Scheme 66).
Compound 169
Compound 169 was
was treated
treated with
with aa second-generation
second-generation Grubbs
Grubbs catalyst
catalyst in
in the
the presence
presence
of p-TsOH acid [90]. It was tested that, in addition to the presence of a
of p-TsOH acid [90]. It was tested that, in addition to the presence of a Lewis acid, Lewis acid, the
the
Following the
Following the synthesis
synthesis of
of tricyclic
tricyclic 170,
170, various
various C-ring
C-ring closing
closing pathways
pathways were
were inves-
inves-
tigated. The γ arylation reaction was unsuccessful, so the Heck reaction was tested.
tigated. The γ arylation reaction was unsuccessful, so the Heck reaction was tested. After After
Molecules 2022, 27, 7322 finding the
finding the optimized
optimized conditions,
conditions, the
the reaction
reaction was
was performed
performed in in the
the presence
presence ofof of
37 two
two56
equivalents of
equivalents of silver
silver carbonate
carbonate inin hot
hot MeCN
MeCN to to give
give compound
compound 171 171 (Scheme
(Scheme 66).
66).
Scheme66.
Scheme
Scheme 66. Method
66. Methodof
Method ofobtaining
of obtaininglysergic
obtaining lysergicacid
lysergic acidproposed
acid proposedby
proposed byLiu
by Liuand
Liu andJia.
and Jia.
Jia.
Finally,the
Finally,
Finally, theBoc
the Bocgroup
Boc groupwas
group wasdeprotected,
was deprotected,
deprotected, andand
and ester
ester
ester hydrolysis
hydrolysis
hydrolysis accompanied
accompanied
accompanied by
by by dou-
double-
dou-
ble-bond
bond
ble-bond isomerization
isomerization
isomerization was
was was performed
performed
performed to obtain
to obtain
to obtain (+)-lysergic
(+)-lysergic
(+)-lysergic acid.
acid.acid.
Strategy
Strategy II.
II. The
The subsequent
subsequent publication
Strategy II. The subsequent publication by the Jia team presents
publication by
by the
the Jia
Jia team
team presents an
presents an optimized
an optimized ver-
optimized ver-
sion
sion of strategy
strategy II and
and compares
compares two
two total
totalsyntheses
syntheses to each
to other;
each
sion of strategy I and compares two total syntheses to each other; one is described as strat- one
other; is
onedescribed
is describedas strat-
as
egy I
strategyin the
I in above
the work,
above plus
work, there
plus is a
there synthesis
is a in
synthesis which
in key
which
egy I in the above work, plus there is a synthesis in which key stages were swapped (strat- stages
key were
stages swapped
were (strat-
swapped
egy II)
egy II) [94].
(strategy [94]. The goal
II) [94].
The goalgoal
The was was
was to further
to further simplify
to further simplify
simplify the the
the synthetic
synthetic
synthetic path
path pathby by
by reducing
reducing
reducing thethe
the effort
effort
effort to
to
protect
to protect
protect functional
functional
functional groups.
groups.
groups. ByBy
By using
using
using 3-chloro-2-iodoaniline,
3-chloro-2-iodoaniline,
3-chloro-2-iodoaniline, it was
it was
it waspossible
possible
possible to simplify
to simplify
to simplify the
the
indole
the coupling
indole coupling to give
to a
givecompound
a compound that could
that be
could directly
be converted
directly
indole coupling to give a compound that could be directly converted into the Heck reac- convertedinto the
into Heck
the reac-
Heck
reaction.
tion. TheThe
tion. The reaction
reaction
reaction started
started
started with
with with simple
simple
simple substrates
substrates
substrates including
including
including chiral
chiralchiral (R)-sulfonamide
(R)-sulfonamide
(R)-sulfonamide 172.172.
172.
The
The first
first step was
was to
to construct
construct aa diene
diene that
that could
could then
then
The first step was to construct a diene that could then be converted to a tetrahydro-be be converted
converted to to
a a tetrahy-
tetrahydro-
dropyridine
pyridine ring
pyridine ringring
by aby
by a metathesis
a metathesis
metathesis reaction.
reaction.
reaction. ForFor
For thisthis
this purpose,
purpose,
purpose, the the
the aldehyde
aldehyde
aldehyde 173,173,
173, (R)-N-tert-
(R)-N-tert-bu-
(R)-N-tert-bu-
butanesulfinamide
tanesulfinamide 172,
tanesulfinamide 172,
172, and and butenyl
and butenyl
butenyl bromide bromide
bromide were were
were reacted,reacted,
reacted, and and
and the the
the chiral chiral allylamine
chiral allylamine
allylamine 174 174
174 was
was
was obtained
obtained
obtained in the
in the inpresence
the presence
presence of of indium
of indium
indium and titanium
and titanium
and titanium (dr[95].
(dr == 7:1)
(dr 7:1) = 7:1)
[95]. [95].
In the
In the nextIn the
next step,next
step, step,
the reac-
the reac-
the
tionreaction
with with bromomethylacrylate
bromomethylacrylate gave gaveisomers
diene diene isomers
175, 175,were
which which were separated
separated by column by
tion with bromomethylacrylate gave diene isomers 175, which were separated by column
column chromatography
chromatography (Scheme (Scheme
67). 67).
chromatography (Scheme 67).
Scheme67.
Scheme
67. Introducingtwo
Introducing twoterminal
two terminaldouble
terminal doublebonds
double bondsinto
bonds intothe
into themolecule
the molecule173
molecule 173in
173 instrategy
in strategyII.
strategy II.
II.
Themetathesis
The
The metathesisreaction
metathesis reaction
gave
reaction gave the
thethe
gave cyclic
cyclic product
product
cyclic 176
176 by
product by
theby
176 the action
action
the action of the
the Grubbs
of the Grubbs
of Grubbs II
II catalyst
II
catalyst
in boilingin boiling
methylene methylene
chloride chloride
[90]. The [90].
-TMS The
group-TMSwasgroup was
deprotected, deprotected,
and
catalyst in boiling methylene chloride [90]. The -TMS group was deprotected, and the al- the and
aldehyde the al-
177
dehyde
was
dehyde 177 was
obtained
177 was obtained
by the by the
the Dess–Martin
Dess–Martin
obtained by Dess–Martin reaction.
reaction. Thereaction. The
obtainedThe obtained
product product is
is a fragment
obtained product is
ofaathe
fragment
target
fragment
of the
the target
target
structure
of with structure withThe
the D-ring.
structure with the D-ring.
the D-ring.
next step The
Thewasnext
next step
thestep was the
coupling
was the coupling
ofcoupling of the
the 3-chloro-2-
3-chloro-2-
the 3-chloro-2-iodoaniline
of
iodoaniline
fragment withfragment
an with
aldehyde 177an toaldehyde
synthesize 177
the to synthesize
indole derivative
iodoaniline fragment with an aldehyde 177 to synthesize the indole derivativethe indole
178 derivative
(Scheme 68). 178
178
(Scheme 68).
(Scheme 68).
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Scheme 68.
Synthesis of
of the
the ABD
ABD tricyclic
tricyclic system
system in
inLiu
Liuand
andJia’s
Jia’sstrategy.
strategy.
Furthersynthesis
Further synthesisrelied
reliedonon manipulating
manipulating thethe functional
functional groups
groups to obtain
to obtain substrate
substrate 180
180the
for forintramolecular
the intramolecular Heck reaction.
Heck reaction. To this To end,this
theend, the nitrogen
nitrogen atom was
atom in indole in indole
protected was
protected
with the Boc with the Boc
group, group,
then then the tert-butanesulfinyl
the tert-butanesulfinyl group was group was removed,
removed, and methyl andwasme-
thyl was introduced
introduced onto the nitrogen
onto the nitrogen of the Double
of the D-ring. D-ring. bondDouble bond isomerization
isomerization was per-
was performed.
Optimization of the Heck
formed. Optimization reaction
of the was performed.
Heck reaction was performed.VariousVarious
reaction conditions
reaction were
conditions
tested (palladium
were tested sources,sources,
(palladium ligands,ligands,
bases, and solvents).
bases, The best The
and solvents). results
best were achieved
results were
using 0.5 equivalents
achieved of Pd2 (dba)
using 0.5 equivalents CHCl
of3Pd 3 , 1.0
22(dba) equivalents
33CHCl of P(t-Bu)of
33, 1.0 equivalents 3 HBF 4 , and
P(t-Bu) 33HBF3.044, equiva-
and 3.0
lents of Cy2 MeN ◦ C. Compound 171, a precursor to lysergic acid, was
equivalents of Cyin dioxane
22MeN at 100 at
in dioxane 100 °C. Compound 171, a precursor to lysergic acid,
obtained
was obtained(Scheme
(Scheme69). 69).
TheTheprocedure
procedure forfor obtaining
obtaining acid
acidtherefrom
therefromisisdescribed
describedin inthe
the
above works [93].
above works [93].
Scheme 69.
Preparation of
of lysergic
lysergicacid
acidprecursor
precursor171.
171.
In
In two
two papers
papers presented
presented by by the
the Jia
Jia group,
group, two
two strategies
strategies for
for the
the preparation
preparation ofof enan-
enan-
tioselective
tioselective acid
acid synthesis of
of (+)-lysergic
(+)-lysergic acid
acid were
were described.
described. Both
Both involved
involved metathesis
metathesis to
to the D-ring, synthesis of the indole derivative (AB-ring), and the closure
the D-ring, synthesis of the indole derivative (AB-ring), and the closure of the C-ring by of the C-ring
by
thethe intramolecular
intramolecular Heck
Heck reaction.
reaction. In strategy
In strategy I, lysergic
I, lysergic acid
acid is is obtained
obtained in 20 steps.
in 20 steps. Strat-
Strategy II allowed for greater convergence of the method and simplified the
egy II allowed for greater convergence of the method and simplified the procedure to just procedure to
just 12 steps.
12 steps.
2.5.
2.5. Other
Other Chemical
Chemical Methods
Methods of
of Obtaining
Obtaining Lysergic
LysergicAcid
Acid
2.5.1. Oppolzer Group Research
2.5.1. Oppolzer Group Research
The Oppolzer group presented the synthesis of (±) lysergic acid, where the C and D
The Oppolzer group presented the synthesis of (±) lysergic acid, where the C and D
rings of the ergoline system were formed through an intramolecular Diels–Alder reaction [85].
ringsisofa the
This ergoline reaction
convergent system were
usingformed through
protected an intramolecular Diels–Alder
4-hydroxymethylindole reaction
as a substrate. The
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[85].
[85]. This
This isis aa convergent
convergent reaction
reaction using
using protected
protected 4-hydroxymethylindole
4-hydroxymethylindole as as aa substrate.
substrate.
The synthetic
synthetic strategy
The synthetic strategy was
was based
strategy based on the preparation
on theonpreparation
was based of
of an of
the preparation an
indoleindole derivative
derivative
an indole substituted
substituted
derivative with
substituted
awith
dienea diene fragment,
fragment, then then connection
connection of of
the the dienophilic
dienophilic system,
system, followed
followed by
by
with a diene fragment, then connection of the dienophilic system, followed by cyclization cyclization
cyclization
(181
(181
(181toto 182, Scheme
182,Scheme
to182, Scheme70) 70) and
70)and isomerization
andisomerization
isomerizationof of the
ofthe double
thedouble bond
doublebond to
bondto the
tothe lysergic
thelysergic acid.
lysergicacid.
acid.
Scheme
Scheme 70.
70. CC
Scheme70. and
Cand
andDD rings
Drings closing
ringsclosing strategy
closingstrategy in
strategyin the
inthe Diels–Alder
theDiels–Alder reaction.
Diels–Alderreaction.
reaction.
The
The synthesis
Thesynthesis started
synthesisstarted
startedwithwith
withthethe conversion
theconversion
conversion of of indole-alcohol
of indole-alcohol
indole-alcohol183 183
183toto the
tothe corresponding
the corresponding
corresponding
bromide
bromide with carbon tetrabromide in the Appel reaction. Then
bromide with carbon tetrabromide in the Appel reaction. Then the obtained product
with carbon tetrabromide in the Appel reaction. Then the
the obtained
obtained product
product waswas
was
treated
treated with
treatedwith phosphine
withphosphine
phosphineto to obtain
toobtain phosphonium
obtainphosphonium
phosphoniumbromide bromide
bromide184 184 [96].
184[96].
[96].
Difficulties
Difficulties
Difficultieswere were encountered
wereencountered
encounteredwith with introduction
withintroduction
introductionof of the
ofthe 2-carbomethoxydiene
the2-carbomethoxydiene
2-carbomethoxydienesystem system
system
into
into the
the indole
indole derivative.
derivative. For
For this
this purpose,
purpose, this
this moiety
moiety was
was masked
masked
into the indole derivative. For this purpose, this moiety was masked with the norbornene with
with the
the norbornene
norbornene
fragment.
fragment.The
fragment. The synthesis
The synthesisof
synthesis of the
of the norbornene
the norbornene derivative
norbornene derivative185
derivative 185 was
185 was performed
was performed using
performed using conditions
using conditions
conditions
from
from the literature; formylation of methylbicyclo[2.2.1]hept-5-enyl-2-carboxylate with
from the
the literature;
literature; formylation
formylation ofof methylbicyclo[2.2.1]hept-5-enyl-2-carboxylate
methylbicyclo[2.2.1]hept-5-enyl-2-carboxylate with
with
methyl
methyl formate in
in the
the presence
presence ofofLDALDA gavegave
thethe expected
expected product
product
methyl formate in the presence of LDA gave the expected product 185 [31]. Adding com- 185 185
[31].[31].
AddingAdding
com-
compound
pound
pound 185 185185intointo
into thethe
the phosphine
phosphine
phosphine salt
salt
salt 184
184 viathe
184via
via theWittig
the Wittigreaction
Wittig reaction allowed
reaction allowed for
allowed for obtaining
obtaining aaa
obtaining
masked
masked diene moiety in product 186. Then, by nucleophilic addition to nitro compound 187,
masked diene
diene moiety
moiety in in product
product 186.186. Then,
Then, by by nucleophilic
nucleophilic addition
addition to to nitro
nitro compound
compound
a187,
fragment of an of electron-poor dienophile was attached to the structure (Scheme 71). This
187, aa fragment
fragment of an an electron-poor
electron-poor dienophile
dienophile was was attached
attached toto the
the structure
structure (Scheme
(Scheme 71).71).
reaction
This was carried out inouttwoinways—using Michael addition to nitroethylene (24% yield)
This reaction was carried out in two ways—using Michael addition to nitroethylene (24%
reaction was carried two ways—using Michael addition to nitroethylene (24%
or in a two-step
yield) synthesis—by reacting a Mannich reaction with formaldehyde, followed
yield) oror in
in aa two-step
two-step synthesis—by
synthesis—by reacting
reacting aa Mannich
Mannich reaction
reaction with
with formaldehyde,
formaldehyde, fol- fol-
by adding
lowed by nitromethane
adding in
nitromethane the presence
in the of acetylenedicarboxylate
presence of (48%)
acetylenedicarboxylate [97].
(48%) [97].
lowed by adding nitromethane in the presence of acetylenedicarboxylate (48%) [97].
Scheme
Scheme 71. Introduction
71. Introduction
Scheme71. of
ofaaamasked
Introductionof masked diene
maskeddiene system
dienesystem into
systeminto the
intothe molecule
themolecule 184.
molecule184.
184.
Nitro
Nitro compound 187 was converted to the oxime 188. The diene moiety was then
Nitro compound
compound 187187 was
was converted
converted toto the
the oxime
oxime 188.
188. The
The diene
diene moiety
moiety was
was then
then
revealed
revealed by
byretro
retroDiels–Alder
Diels–Alderthermal
thermalreaction, yielding
reaction, keykey
yielding intermediate proposed
181181
intermediate proposed by
revealed by retro Diels–Alder thermal reaction, yielding key intermediate 181 proposed
Oppolzer.
by The intramolecular reaction required keeping the concentration of the interme-
by Oppolzer.
Oppolzer. The
The intramolecular
intramolecular reaction
reaction required
required keeping
keeping the
the concentration
concentration ofof the
the inter-
inter-
diate very
mediate lowlow
throughout thethe
reaction. The dienophile/diene system generated in situ,
mediate very low throughout the reaction. The dienophile/diene system generated in
very throughout reaction. The dienophile/diene system generated in situ,
situ,
thus,
thus, underwent aa Diels–Alder reaction to give the tetracyclic 182 system, as a mixture of
thus, underwent
underwent a Diels–Alder
Diels–Alder reaction
reaction to
to give
give the
the tetracyclic
tetracyclic 182
182 system,
system, as
as a
a mixture
mixture of of
diastereomers.
diastereomers.
diastereomers.
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The formal
The
The formal synthesis
formal synthesis of
synthesis of lysergic
of lysergic acid
lysergic acid was
acid was completed
was completed by
completed by replacing
by replacing N-methoxy
replacing N-methoxy group
N-methoxy group
group
withmethyl
with
with methylgroup
methyl groupusing
group usingmethyl
using methylfluorosulfonate,
methyl fluorosulfonate,followed
fluorosulfonate, followedby
followed byhydrogenolysis
by hydrogenolysisand
hydrogenolysis andhydroly-
and hydrol-
hydrol-
ysis
sis (Scheme
(Scheme 72).
72). NMR
NMR analysis
analysis confirmed
confirmed the
the identity
identity ofof the
the obtained
obtained product
product
ysis (Scheme 72). NMR analysis confirmed the identity of the obtained product [58]. [58].
[58].
Scheme 72.
Preparation of
of lysergic
lysergic acid
acid by
by the
the Oppolzer
Oppolzer procedure.
procedure.
Scheme 72. Preparation of lysergic acid by the Oppolzer procedure.
2.5.2. Research
2.5.2.
2.5.2. Research Carried
Research Carriedout
Carried Outby
Out byInuki,
by Inuki,Iwata.
Inuki, Iwata.and
Iwata. andOhno
and Ohno
Ohno
Thegroup
The
The groupled
group ledby
led by Ohno
by Ohno was
Ohno was investigating
was investigating the
investigating the preparation
the preparation of
preparation of heterocyclic
of heterocyclic compounds
heterocyclic compounds
compounds
by
by reaction
by reaction of allenes. These
allenes.These
reaction of allenes. These methods
methods
methods were
were
were used
usedused to synthesize
to synthesize
to synthesize lysergic acid
lysergic
lysergic via
acidacid two
via two syn-
via syn-
two
thetic pathways.
synthetic
thetic pathways.
pathways. The key
The key reactions
The reactions
key reactions in these
in these pathways
in these
pathways were the
pathways
were the
were preparation of the
the preparation
preparation of the cumu-
cumu-
of the
lative
cumulativedouble bond
double system
bond giving
system the
giving allene,
the followed
allene, by
followed
lative double bond system giving the allene, followed by the domino reaction of the the
by domino
the reaction
domino of
reaction the pal-
of pal-
the
ladium-catalyzed
palladium-catalyzed cyclization
cyclization of the
of allene
the alleneto form
to form a new
a newstereogenic
stereogenic
ladium-catalyzed cyclization of the allene to form a new stereogenic center. This is due to center. This
center. is
This due
is dueto
the
to thetransfer
transferofofthe axial
the axial chirality
chirality ofofthe
the C=C=C
C=C=C system
system to
tothe
the asymmetric
the transfer of the axial chirality of the C=C=C system to the asymmetric carbon [98–100].asymmetric carbon
carbon [98–100].
StrategyI.I.
Strategy
Strategy I.The
Thesynthesis
The synthesisofof
synthesis lysergic
of lysergic
lysergic acid, lysergol,
acid,
acid, lysergol,
lysergol, andandisolysergol
and waswas
isolysergol
isolysergol carried
was out. The
carried
carried out.
out.
synthetic
The synthetic strategy was based on the synthesis of allenes by Claisen rearrangementthe
The strategy
synthetic was
strategy based
was on
based theon synthesis
the of
synthesis allenes
of by
allenes Claisen
by rearrangement
Claisen rearrangement of of
of
corresponding
the corresponding enol ether,
enol followed
ether, by cyclization
followed by of the CD
cyclization of rings
the viarings
CD a palladium-catalyzed
via a palladium-
the corresponding enol ether, followed by cyclization of the CD rings via a palladium-
domino
catalyzed reaction
domino [98].
reaction [98].
[98].
catalyzed domino reaction
The
The preparation
preparation ofofallenes
allenes waswas proposed
proposed bybystarting
startingthethesynthesis
synthesisof 4-bromoindole
of 4-bromoindole
4-bromoindole 61.
The preparation of allenes was proposed by starting the synthesis of
Reactions
61. Reactions from
Reactions from the
from the literature
the literature can
literature can afford
can afford the
afford the protected
the protected bromomethylindole
protected bromomethylindole
bromomethylindole 189. 189. Using
189. Using
Using
61.
n-butyllithium,
n-butyllithium, aacoupling
coupling reaction
reaction was
was performed
performed substituting
substituting thethe
indole
indolewith acetylenecar-
with acetylene-
n-butyllithium, a coupling reaction was performed substituting the indole with acetylene-
baldehyde,
carbaldehyde, withwitha source that was thioacetal 190.190.Compound
Compound190 190was
wasobtained
obtainedin in 96%
carbaldehyde, with aa source
source that
that was
was thioacetal
thioacetal 190. Compound 190 was obtained in 96%
96%
yield
yield (Scheme
(Scheme 73).
73).
yield (Scheme 73).
Scheme73.
Scheme
73. Synthesisof
Synthesis ofthioacetal
of thioacetal190
thioacetal 190from
190 frombromoindole.
from bromoindole.
bromoindole.
Then,
Then,bybyhydrolysis
hydrolysis ofof
thethe
thioacetal reduction
190,190,
thioacetal withwith
reduction sodium borohydride,
sodium removal
borohydride, re-
Then, by hydrolysis of the thioacetal 190, reduction with sodium borohydride, re-
of the TMS
moval of protecting
of the
the TMS group,
TMS protecting and
protecting group, addition
group, and of
and additionmethyl
addition of propiolate,
of methyl the
methyl propiolate, enol
propiolate, the ether
the enol 191
enol etherwas
ether 191
191
moval
obtained.
was In theInnext
obtained. the reaction,
next the reduction
reaction, the and protection
reduction and of the
protection ofalcohol
the formed
alcohol withwith
formed the
was obtained. In the next reaction, the reduction and protection of the alcohol formed with
TIPS-protected
the TIPS-protectedgroup
TIPS-protected 192 was
group carried
192 was out (Scheme
was carried
carried 74). The
out (Scheme
(Scheme 74). compound
The compound
compoundprepared in this
prepared in
the group 192 out 74). The prepared in
way
this was awas
way substrate
a for the
substrate forClaisen
the rearrangement
Claisen rearrangementreaction, leading
reaction, to thetoallene
leading the 193. 193.
allene
this way was a substrate for the Claisen rearrangement reaction, leading to the allene 193.
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Scheme 74. Enolate ether 192 synthesis.

Scheme 74. Enolate
Scheme 74. Enolate ether 192 synthesis.
ether 192 synthesis.
Optimizing the
Optimizing conditions led the authors to aa procedure that used microwave radi-
Optimizing the
the conditions
conditions led
led the
the authors
authors to
to a procedure
procedure that that used
used microwave
microwave radi-
radi-
ation. A
ation. diastereomeric mixture of products 193 was obtained,
obtained, whichwhich was
was used
used without
ation. A diastereomeric mixture of products 193 was obtained, which was used without
A diastereomeric mixture of products 193 was without
further purification.
further purification. TheMitsunobu
Mitsunobu reaction with NsNH 2, analogous
with with TsNHF moc,
further purification.The
The Mitsunobu reaction with
reaction NsNH
with NsNH2 , analogous TsNHF
2, analogous with TsNHF moc , gave
moc,
gave N-nosyl
N-nosyl and N-tosyl
and N-tosyl derivatives
derivatives 194
194 (Scheme (Scheme 75).
75). Better Better results
resultsresults of the following
of the following re-
reactions
gave N-nosyl and N-tosyl derivatives 194 (Scheme 75). Better of the following re-
actions
have have
been been achieved
achieved by usingbya using
tosyl a tosyl group.
group.
actions have been achieved by using a tosyl group.
Scheme 75. Obtaining allene in strategy I.

Scheme 75.
Obtaining allene
allene in
in strategy
strategy I.I.
The preparation of the tetracyclic ergoline structure was accomplished by palladium-

The
The preparation
preparation of of the
the tetracyclic
tetracyclic ergoline structure
structure was accomplished by palladium-
catalyzed domino cyclization. The best conditions were selected by testing different lig-
catalyzed
catalyzed domino cyclization.
cyclization. The Thebest
best conditions
conditions werewere selected
selected by by testing
testing different
different lig-
ands and bases. The best yield and diastereomeric excess (dr = 83:17 in favor of the desired
ligands and bases. The best yield and diastereomeric excess (dr = 83:17
ands and bases. The best yield and diastereomeric excess (dr = 83:17 in favor of the desired in favor of
diastereomer)
the was obtained
desired diastereomer) waswith 5% mol
obtained Pd(PPh 3)4 and 3 eq of potassium carbonate in
diastereomer) was obtained with 5% molwith 5% mol
Pd(PPh Pd(PPh
3)4 and )4 potassium
3 eq 3of and 3 eq ofcarbonate
potassium in
hot DMF. in hot DMF.
carbonate
hot DMF.
Tosyl-protected compound
Tosyl-protected compound 195 was was a lysergic acid acid precursor. Cleavage
Cleavage of thethe TIPS
Tosyl-protected compound 195 195 was aa lysergic
lysergic acid precursor.
precursor. Cleavage of of the TIPS
TIPS
group,
group, oxidation of the resulting alcohol in the Dess–Martin procedure, and esterification
group, oxidation
oxidation ofof the
the resulting
resulting alcohol
alcohol in
in the
the Dess–Martin
Dess–Martin procedure,
procedure, andand esterification
esterification
gave the
gave product
product196.
196.Then,
Then,the
theNH groups were deprotected, and thethe
ester 51 used in the
gave the
the product 196. Then, the NHNH groups
groups were
were deprotected,
deprotected, andand ester
the ester 51 used
51 used in
in the
synthesis
the of
synthesislysergic
of acid
lysergic was
acid obtained
was (Scheme
obtained (Scheme76), which
76), can
which be
can converted
be convertedinto the
into de-
the
synthesis of lysergic acid was obtained (Scheme 76), which can be converted into the de-
sired, optically
desired, pure
optically pure acid byby
acid alkaline and
alkaline andacid hydrolysis.
acid hydrolysis.
sired, optically pure acid by alkaline and acid hydrolysis.
Scheme 76. Preparation of lysergic acid ester 51 proposed by Inuki, Iwata, and Ohno.
Scheme 76.
Preparation of
of lysergic
lysergicacid
acidester
ester51
51proposed
proposedby
byInuki,
Inuki,Iwata,
Iwata,and
andOhno.
Ohno.
Strategy II.II. The allene

allene was obtained
obtained by the
the reductive coupling
coupling reaction ofof aziridine
Strategy II.The
Strategy The allenewas was obtained by
by thereductive
reductive coupling reaction
reaction of aziridine
aziridine
palladium and
palladium and the creation of the C-C bond between the indole derivative and oxazinane,
palladium and the the creation
creation ofof the
the C-C
C-C bond
bond between
between the
the indole
indole derivative
derivative and
and oxazinane,
oxazinane,
followed by
followed by the Myers
Myers reaction [100].
[100].
followed by the the Myersreaction
reaction [100].
First,
First, the materials for the coupling were
were prepared. ForFor this purpose,
purpose, bromoindole
First, the
the materials
materials forfor the
the coupling
coupling were prepared.
prepared. For this
this purpose, bromoindole
bromoindole
aldehyde
aldehyde 202 was prepared
was prepared from
prepared from bromoindole
frombromoindole 61,
bromoindole61, using the
usingthe coupling
thecoupling reaction
coupling of allyl
reaction al-
aldehyde 202202 was 61,using reaction of of allyl
allyl al-
cohol according to the procedure in the literature [101], protection of the nitrogen atom in
cohol according to the procedure in the literature [101], protection of the nitrogen atom in
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56
alcohol according to the procedure in the literature [101], protection of the nitrogen atom
inthe
the indole,
indole, andand
then then oxidative
oxidative cleavage
cleavage of olefin
of olefin
olefin to201
201 to to aldehyde
aldehyde 202. The202.
The Thesubstrate
second second
the indole, and then oxidative cleavage of 201 aldehyde 202. second substrate
substrate
was the was
the chiral the chiral
chiral oxazinane oxazinane
oxazinane derivative derivative
derivative 200.
200. It
It was 200. It
was prepared was
prepared from prepared
from optically from
optically pure optically
pure aziridine pure
aziridine 198
was 198
aziridine
(97% ee),198 (97%
which, inee),
turn,which,
is in turn,
obtainable is
from obtainable
(S)-Garner from (S)-Garner
aldehyde 197 inaldehyde
a four-step 197 in a
synthe-
(97% ee), which, in turn, is obtainable from (S)-Garner aldehyde 197 in a four-step synthe-
four-step
[102].synthesis
sis [102]. By treating
treating [102]. By treating
aziridine aziridine
198 with
with 198 with a catalytic amount compound
of a palladium
sis By aziridine 198 aa catalytic
catalytic amount
amount of aa palladium
of palladium compound with with
compound
InI in with
in aa mixture
mixture of InI in a mixture
of THF/HMPA
THF/HMPA and of THF/HMPA
and formalin,
formalin, the and formalin,
the amino alcohol the
alcohol 199 amino
199 was alcohol
was obtained, 199 was
obtained, which
which
InI
obtained, which could be easily changed the amino
intoderivative
oxazinane derivative (Scheme
200Both 77).
could
could be easily
be easily changed
changed into the
into the oxazinane
oxazinane 200 (Scheme 77). iodinated
Both iodinated and free terminal alkyne enable derivative
the coupling 200 (Scheme
reaction 77).
to be Both out;
carried iodinated
how-
and free
and free terminal
terminal alkyne
alkyne enable
enable the
the coupling
coupling reaction
reaction to be carried
carried out;
out; however,
however, byby in-
in-
ever, by introducing iodine, the efficiency and selectivitytoofbe the coupling process increase.
troducing iodine, the efficiency and selectivity of the coupling
troducing iodine, the efficiency and selectivity of the coupling process increase. process increase.
Scheme77.
Scheme
Scheme 77.Synthesis
77. Synthesisofof
Synthesis ofmaterials
materialsfor
materials forthe
for thecoupling
the couplinginin
coupling instrategy
strategyII.II.
strategy II.
Withthe
With
With theprepared
the preparedsubstrates
prepared substrates200
substrates 200and
200 and202
and 202inin
202 inhand,
hand,the
hand, theprocess
the processofof
process oftheir
theircombination
their combination
combination
was
was started. The
started. The coupling
couplingreaction
reactionof these
of fragments
these fragments was carried
was out
carried using
out
was started. The coupling reaction of these fragments was carried out using nickel nickel
using chloride
nickel chlo-
chlo-
and
ridechromium
and chloride.
chromium A
chloride.racemic
A mixture
racemic of
mixture alcohol
of 203
alcohol was
203 wasobtained.
obtained.
ride and chromium chloride. A racemic mixture of alcohol 203 was obtained. Dess–Martin Dess–Martin
Dess–Martin
oxidation
oxidationfollowed
oxidation followedby
followed byreduction
by reductionwith
reduction with(R)-Alpine
with (R)-AlpineBorane
(R)-Alpine Boranemade
Borane madeitit
made itpossible
possibleto
possible toobtain
to obtainthe
obtain the
the
desired asymmetric
desired asymmetric
desired product
asymmetric product 204
product 204 from
204 from the
from the racemic
the racemic alcohol
racemic alcohol (dr
alcohol (dr= 95:5)
(dr == 95:5)(Scheme
95:5) (Scheme 78).
(Scheme 78).78).
Scheme 78.
Scheme 78. Reaction
Reaction leads
leads to an
an asymmetric
asymmetric alcohol
alcohol 204.
204.
Scheme 78. Reaction leads totoan asymmetric alcohol 204.
Molecules2022,
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43 of 56
Alcohol204
Alcohol 204was
was stereoselectively
stereoselectively converted
converted to allene
to the the allene 205
205 by thebyMyers
the Myers
method method
[103],
[103], using nitrobenzenesulfonyl hydrazine under Mitsunobu conditions.
using nitrobenzenesulfonyl hydrazine under Mitsunobu conditions. Then the oxazinane Then the oxa-
zinane
was was with
cleaved cleaved with
PTSA. PTSA.
The The 206
product product 206 was with
was obtained obtained with a diastereomeric
a diastereomeric ex-
excess (94:6),
cessthe
but (94:6), but the
mixture wasmixture was notAseparated.
not separated. A dominoreaction
domino cyclization cyclization reaction
through throughcom-
palladium pal-
ladiumwas
pounds compounds
performedwas performed
under optimizedunder optimized
conditions (5 mol%conditions
Pd(PPh3 )(5 4 , Kmol%
2 CO3 , Pd(PPh
and DMF 3)4,
CO◦3,C).
atK2100 andThe
DMFanalogous reaction
at 100 °C). for the second
The analogous epimeric
reaction product
for the second was also checked
epimeric productusing
was
also checked
reduction with using reduction
(S)-borane. with (S)-borane.
The cyclization reactionThe
from cyclization
the allenereaction
gave thefrom the allene
corresponding
diastereoisomer 207 withdiastereoisomer
gave the corresponding high selectivity.207
This compound
with is the key
high selectivity. intermediate
This compoundinisthethe
approach used by in
key intermediate thethe
Ohno group used
approach (Scheme 79).Ohno group (Scheme 79).
by the
Scheme79.
Scheme 79.Obtaining
Obtainingallene
alleneininstrategy
strategyII.II.
The
Theprimary
primaryalcohol 207was
alcohol207 wasoxidized
oxidizedwith
withaaDess–Martin
Dess–Martinreagent
reagentandandchlorite.
chlorite.The
The
esterification was then carried out to the known racemic methyl ester, of which both amine
esterification was then carried out to the known racemic methyl ester, of which both amine
functions
functionswere
wereprotected
protectedwith
withtosyl
tosyl(196),
(196),which
whichcould
couldbe
betransformed
transformedintointolysergic
lysergicacid
acid
(Scheme
(Scheme80)80)[64,70,98].
[64,70,98].
Scheme80.
Scheme 80.Obtaining
Obtainingintermediate
intermediate196
196ininstrategy
strategyII.
II.
The
Theabove
abovepublication
publicationdescribes
describes methods
methods for for the
the synthesis
synthesis of of other
other ergot
ergot alkaloids,
alkaloids,
lysergol
lysergolandandisolysergol.
isolysergol.The Thetotal
totalsynthesis
synthesisof oflysergic
lysergicacidacidconsists
consistsof of19
19steps,
steps,and
andthe
the
overall yield is 1.1%. The starting material was Garner’s aldehyde. The
overall yield is 1.1%. The starting material was Garner’s aldehyde. The innovation of this innovation of this
synthetic
syntheticstrategy
strategyinvolves
involvesthe theconstruction
constructionofofthe theDDring
ringas asaaresult
resultofofcatalytic
catalyticcyclization
cyclization
of
of the allene. Further work by Ohno’s team boiled down to new methodsof
the allene. Further work by Ohno’s team boiled down to new methods ofobtaining
obtainingthethe
above
aboveallene,
allene,which
whichcan canthen
thenbebeeasily
easilytransformed
transformedinto intothe
theintermediate
intermediate51. 51.
Strategy
StrategyIII. Strategy
III. StrategyIII of
IIIobtaining lysergic
of obtaining acid—specifically
lysergic acid—specifically of intermediate 51—was
of intermediate 51—
based on similar assumptions as strategy II. The bromoindole derivative
was based on similar assumptions as strategy II. The bromoindole derivative 61 and the 61 and the corre-
sponding alkynealkyne
corresponding were prepared,
were prepared,and the coupling
and reaction
the coupling was performed.
reaction The resulting
was performed. The re-
alkyne was converted to an allene, which could be converted to the corresponding
sulting alkyne was converted to an allene, which could be converted to the corresponding interme-
diate. The newThe
intermediate. ideanew
wasidea
to obtain
was toa chiral
obtainalcohol,
a chiralnot by annot
alcohol, asymmetric oxidationoxidation
by an asymmetric reaction,
but by a regioselective epoxide opening sequence. For this purpose,
reaction, but by a regioselective epoxide opening sequence. For this purpose, the reactants the reactants were
modified—the synthesis started with bromoindole and the corresponding sulfonamide
were modified—the synthesis started with bromoindole and the corresponding sulfona-
terminal (S)-alkyne, as known in the literature [99].
mide terminal (S)-alkyne, as known in the literature [99].
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Commercially available 4-bromoindole 61 was formylated by the Vilsmeier–Haack

reaction [104], followed
Commercially
Commercially by treatment
available
available of resulting
4-bromoindole
4-bromoindole wasaldehyde
61 was
61 formylated
formylated208bywith
by theCBr
the 4, which gave
Vilsmeier–Haack
Vilsmeier–Haack
reaction
reaction [104],
[104], followed
dibromoolefin 209. Usingby
followed thetreatment
by of
ofresulting
Uenishi method
treatment [105],aldehyde
resulting followed
aldehydeby 208
208 with
the CBr
CBr4 4,, which
Sonogashira
with gave
coupling
which gave
dibromoolefin
of the known chiral
dibromoolefin 209.Using
209. the
alkyne,
Using Uenishi
thewhich can
Uenishi method [105],
[105],followed
be prepared
method from by
bythe
theSonogashira
(S)-Garner
followed aldehyde 197
Sonogashira coupling
(analo-
coupling
of
ofthe
goustheknown
toknown chiral
strategy I),alkyne,
chiral aalkyne,which
compoundwhichcan
wasbeobtained
can prepared
be from (S)-Garner
containing
prepared from aldehyde
a triple
(S)-Garner and 197 (analogous
a double
aldehyde 197bond at
(analo-
to strategy
adjacent I), a compound
carbon atoms—enyne
gous to strategy was
I), a compound obtained
210was containing
(Scheme a triple and a double bond at
81).containing a triple and a double bond at
obtained adjacent
carbon
adjacent atoms—enyne
carbon atoms—enyne 210 (Scheme 21081).
(Scheme 81).
Scheme 81. Synthesis of enyne 210 from bromoindole.

Scheme81.
Scheme 81.Synthesis
Synthesisof
ofenyne
enyne210
210from
frombromoindole.
bromoindole.
The epoxidation of enyne 210 was a challenging step. Various epoxidizing agents
wereThetested,
The but neither
epoxidation
epoxidation the
of enyne
of enyne use210
of the
210 was
was Shi catalyst
aachallengingnor step.
challenging the m-CPBA
step. Variousacid
Various allowed agents
epoxidizing
epoxidizing for ob-
agents
taining
were the epoxide
were tested,
tested, 211 in
but neither theause
the satisfactory
use ofofthe
theShiyield.
Shi Only
catalyst
catalyst the
nor
nor optimization
thethe m-CPBA
m-CPBA ofallowed
acid
acid theallowed
conditions
for for
ob-
(presence
obtaining
taining the ofepoxide
the nepoxide
Bu4NHSO 211in
211 4,inoxone) allowedyield.
aasatisfactory
satisfactory the yield
yield. Onlyofthe
Only theoptimization
product to be ofover
of the 70%, with
the conditions
conditions
a(presence
diastereomeric
(presence ofofnnBu
Bu4ratio
NHSO
4NHSOof 482:18.
4, ,oxone)Theallowed
oxone) OH group
allowed thewas
the protected
yield
yieldofofthe with TIPSOT,
theproduct
product toto
bebe and70%,
over
over then
70%, chiral
with a
with
diastereomeric
alcohol ratio
212 was obtained
a diastereomeric of 82:18. The
by ring
ratio of 82:18. OH group
Theopening
OH group was
withwas protected
Lewis with
acid (ZnCl
protected TIPSOT,
or Zn(OTf)
with 2TIPSOT, and then
and2),then chiral
retaining
chiral
alcohol
the 212
excess
alcohol was
wasobtained
obtainedby
212diastereoisomer. ring
ringopening
byAlcohol 212 was
opening with Lewis
Lewisacid
converted
with (ZnCl
(ZnCl2 2or
(analogycal
acid toZn(OTf)
or Zn(OTf)22),
strategy ),retaining
II) in allene
retaining
the
theexcess
206 using diastereoisomer.
excess a modified Myers
diastereoisomer. Alcohol
Alcohol 212
reaction was
212via converted
converted(analogycal
wasnitrobenzenesulfonyl totostrategy
(analogycalhydrazine II)
II)in
strategy(Scheme inallene
82)
allene
206using
206
[106].usinga amodified
modified Myers
Myers reaction via nitrobenzenesulfonyl
reaction via nitrobenzenesulfonyl hydrazine (Scheme
hydrazine 82) [106].
(Scheme 82)
[106].
Scheme 82.
Obtaining allene
allene in
in strategy
strategy III.
III.
Scheme 82. Obtaining allene in strategy III.
In
In summary,
summary, strategy III III used
usedthe thefollowing
followingreactions:
reactions: obtaining
obtaining a bromoolefin,
a bromoolefin, a
a de-
derivative
rivative of indole
of indole 209;
In summary, 209; then,
then,III
strategy via
viaused the
the UenishiUenishi reaction
reaction
the following and Sonogashira
and Sonogashira
reactions: coupling
obtaining acoupling to
to a termi-
bromoolefin, a
a de-
terminal
nal
rivative alkyne,
alkyne,
of indole the
the enyne, enyne, thus
thus via
209; then, obtained,
obtained, was oxidized
was oxidized
the Uenishi reaction andby anby an asymmetric
asymmetric
Sonogashira epoxidation
epoxidation
coupling reac-
to a termi-
reaction,
tion, andand
nal alkyne, the
thethe alkene
alkene
enyne, oxide
oxide
thus was was opened
opened
obtained, byby
was regioselective
regioselective
oxidized reduction
by anreduction tothe
to
asymmetric the chiral alcohol.
chiral
epoxidation alcohol.
reac-
This
tion,alcohol,
and thewith a carbon–carbon
alkene oxide was openedtriple bond in its structure,
by regioselective was converted
reduction into analcohol.
to the chiral allene
Molecules 2022, 27, 7322 45 of 56

This alcohol, with a carbon–carbon triple bond in its structure, was converted into an al-
lene alcohol,
This in a modifiedwith aMyers reaction, triple
carbon–carbon which,bond
analogically to strategy
in its structure, I and II, can
was converted intobeancon-
al-
verted into intermediate 51, and, further, into (+)-lysergic acid.
lene in a modified Myers reaction, which, analogically to strategy I and II, can be con-
in a modified
verted Myers reaction,
into intermediate which,
51, and, analogically
further, to strategy
into (+)-lysergic I and II, can be converted into
acid.
intermediate
2.6. Attempts 51, and, further,
of Obtaining into (+)-lysergic
Lysergic Acid by Other acid.
Methods
2.6. Attempts
2.6.1. Padwa of of Obtaining
Group Lysergic Acid by Other Methods
Research
2.6. Attempts Obtaining Lysergic Acid by Other Methods
2.6.1.In
2.6.1. Padwa
Padwa Group
1995,Group Research
the Albert Padwa research group developed a new synthetic pathway that
Research
could Ineventually
In 1995, the
1995, lead toPadwa
the Albert
Albert lysergic
Padwa acid [107].
research
research group developed
group developed aa new new synthetic
synthetic pathway
pathway thatthat
could First, it
eventuallywas shown
lead to that the
lysergic
could eventually lead to lysergic acid [107]. intramolecular
acid [107]. dipolar cycloaddition of isomuenchnone
by an olefin
First,
First, or
itit was
was anshown
alkynethat
shown leads
that thetointramolecular
the the quinoline structure—the
intramolecular C and Dof
dipolar cycloaddition
dipolar cycloaddition ring
of of ergot alka-
isomuenchnone
isomuenchnone
loids.
by an
by Subsequently,
an olefin
olefin or oran a
analkyne12-step
alkyneleads synthesis
leadstoto thethe was
quinolinecarried
quinoline out, starting
structure—the
structure—the from
C and the
D ring
C and known tricyclic
of ergot
D ring of alka-
ergot
olefin 215,
alkaloids. through
loids. Subsequently,
Subsequently,diazoimide
a 12-step 214,
synthesis
a 12-step to lysergic acid
was carried
synthesis derivative
out, starting
was carried 213 (Scheme
from the
out, starting 83).
known
from Unfortu-
the tricyclic
known
nately,215,
olefin
tricyclic the
olefindouble-bond
through
215, through isomerization,
diazoimide diazoimide which
214, to lysergic
214, would
to acid lead
acid to
derivative
lysergic a lysergic
213 (Scheme
derivative 213acid
83).structure,
Unfortu-
(Scheme 83).
could
nately, not
thebe carried
double-bond out. isomerization, which would lead
Unfortunately, the double-bond isomerization, which would lead to a lysergic acid to a lysergic acid structure,
could not
could not be
be carried
carried out.
out.
Scheme 83. Retrosynthetic analysis proposed by Padwa.

Scheme 83.
Retrosynthetic analysis
analysis proposed
proposedby
byPadwa.
Padwa.
The synthesis began with the known protected tetrahydrobenzoindole 215. Ozonol-
ysis The
wassynthesis
The performed
synthesis began
began with
withthe
followed byknown
the protected
reduction
known with tetrahydrobenzoindole
protected sodium borohydride. 215.
tetrahydrobenzoindole Ozonolysis
A diol
215. was ob-
Ozonol-
was performed
tained, which followed
was by
selectivelyreduction
oxidized, with sodium
followed by borohydride.
a Wittig A
reaction,diol
ysis was performed followed by reduction with sodium borohydride. A diol was 216. to was
give obtained,
olefin ob-
which
In the was
tained,next
whichselectively
three
wassteps, oxidized,
selectively 217followed
amide oxidized, by a Wittig
was obtained
followed from
by a thereaction,
olefin
Wittig to give
using
reaction, olefin
thegive
to Jones 216. In
reagent,
olefin 216.
the next three steps,
carbonyldiimidazole,
In amide
the next three steps,and 217 was
methylamine.
amide obtained from
Diazoimide
217 was obtained the
from 214 olefin
the was using
olefinpreparedthe
using the Jones
byJones reagent,
the action
reagent,of
carbonyldiimidazole,
acid chloride and azide.
carbonyldiimidazole, and
and methylamine.
This compound was
methylamine. Diazoimide 214 was
used to study
Diazoimide 214 theprepared
was cyclization
prepared by the
the action
byreaction of
using
action of
acid chloride
the Rh(II)
acid and
and azide.
catalyst
chloride (Scheme
azide. This compound
84)
This [108].
compound was
was used
used to
to study
study the
the cyclization
reaction using
using
the Rh(II) catalyst (Scheme 84) [108].
the Rh(II) catalyst (Scheme 84) [108].
Scheme84.
Beginningof
ofthe
thesynthesis
synthesisproposed
proposedby
byPadwa.
Padwa.
Scheme 84. Beginning of the synthesis proposed by Padwa.
Thecyclization
The cyclizationconditions
conditionshavehave been
been optimized
optimized by selecting
by selecting the best
the best catalyst.
catalyst. The
The best
selectivity was achieved
best selectivity
The cyclization usingusing
was achieved
conditions perfluorobutyrate
have (pfb)(pfb)
perfluorobutyrate
been optimized as
bythe
asrhodium
the rhodium
selecting thecatalyst
best ligand.
catalyst ligand.
catalyst. The
best The
The conversion
conversion
selectivity of
of the
the oxygen
was achieved oxygen bridge
bridge containing product
containing(pfb)
using perfluorobutyrate as the215
product 215 toto the
rhodium thecorresponding
corresponding
catalyst ligand.
enamide
enamide 216
216 was performed
performed using
using boron
boron fluoride
fluoride as
as a a Lewis
Lewis acid.
acid. The The enamide,
enamide,
The conversion of the oxygen bridge containing product 215 to the corresponding thusthus
ob-
obtained, was
tained, was
enamide treated
216treated with thiocarbonate
with thiocarbonate
was performed using boron in benzene
in fluoride
benzeneas by performing
bya performing the Barton–McCombie
Lewis acid. TheBarton–McCombie
enamide, thus ob-
reaction [109].
tained, was Chiral
treated withester 213 was obtained
thiocarbonate in the
in benzene by form of a mixture
performing of diastereoiso-
the Barton–McCombie
mers. Unfortunately, all attempts to isomerize the double bond have been unsuccessful
(Scheme 85).
reaction [109]. Chiral ester 213 was obtained in the form of a mixture of diastereoisomers.
Molecules 2022, 27, 7322 46 of 56
Unfortunately, all attempts to isomerize the double bond have been unsuccessful (Scheme
85).
Scheme85.
Scheme 85.Continuation
Continuationof
ofthe
thesynthesis
synthesisproposed
proposedby
byPadwa.
Padwa.
Inconclusion,
In conclusion,thethe total
total synthesis
synthesis of ergot
of ergot alkaloids—lysergic
alkaloids—lysergic acidpaspalic
acid and and paspalic acid—
acid—could
could
not not be completed.
be completed. At the
At the same same
time, thetime, theproposed
method method proposed
by Padwaby Padwa
allows for allows for the
the closure of
the C and D rings to the ergoline structure, and further research may lead to the achievement
closure of the C and D rings to the ergoline structure, and further research may lead to the of
the assumed goal.
achievement of the assumed goal.
2.6.2.
2.6.2.Parsons
ParsonsGroup
GroupResearch
Research
One
One year after the Padwa
year after the Padwa research,
research, an
an article
article by
by the
the Parsons
Parsons group
group was
was published,
published,
which
which presented the results of new methods of performing tandem reactionsfor
presented the results of new methods of performing tandem reactions forthe
thering
ring
closure in natural compounds and their analogues [110]. This publication
closure in natural compounds and their analogues [110]. This publication summarizes the summarizes
the team’s
team’s achievements,
achievements, including
including the the possibility
possibility of closing
of closing three-
three- andand four-membered
four-membered sys-
systems
tems leading to ergoline, as presented previously [111]. There are also studies conducted
leading to ergoline, as presented previously [111]. There are also studies conducted
by ‚ u ‚
Ȍzlȕ and
byOzl and Cladingboel,
Cladingboel, whowho attempted
attempted toto synthesize
synthesize lysergic
lysergicacid
acid[112].
[112]. In
In these
these studies,
studies,
free
free radical reactions obtained by homolytic cleavage of a carbon–bromine bond
radical reactions obtained by homolytic cleavage of a carbon–bromine bond with
withaa
hydride were used. Radical reactions allow single or double (tandem) cyclization reaction
hydride were used. Radical reactions allow single or double (tandem) cyclization reaction
to take place.
to take place.
The starting material was 2-bromo-3-nitrobenzoic acid 217. As a result of the multi-
The starting material was 2-bromo-3-nitrobenzoic acid 217. As a result of the multi-
stage synthesis, the aldehyde 218 was obtained, which was then reacted with amines to
stage synthesis, the aldehyde 218 was obtained, which was then reacted with amines to
give compounds 219 and 221.
give compounds 219 and 221.
Cladingboel proposed a radical cyclization reaction using MPM-protected compound 219.
Cladingboel proposed a radical cyclization reaction using MPM-protected com-
Tandem cyclization, performed with tributyltin hydride and AIBN, resulted in reduced to a
pound 219. Tandem cyclization, performed with tributyltin hydride and AIBN, resulted
five-membered structure of the D-ring 220.
in reduced to a five-membered ‚ structure of the D-ring 220.
‚ used methyl 2-(methylamine)acrylate to introduction
Continuing this work, Ozl u
Continuing this work, Ȍzlȕ used methyl 2-(methylamine)acrylate to introduction an
an ester group in compound 221. Operating at elevated temperature, cyclization of the
ester group in compound 221. Operating at elevated temperature, cyclization of the six-
six-membered D-ring was performed; however, the radical reaction also led not to lysergic
membered
acid D-ring
but to its was derivative
saturated performed;223 however,
(Schemethe86).radical reaction also led not to lysergic
acid but to its saturated derivative 223 (Scheme 86).
Molecules 2022,27,
Molecules2022, 27,7322
47 56
Scheme 86.
Scheme 86. Parsons
Parsons group
group synthetic
syntheticstrategies.
strategies.
2.7.
2.7. Biosynthetic
Biosynthetic Pathways
Pathways of of Lysergic
LysergicAcid
Acid
The pioneer of the topic of ergot
The pioneer of the topic of ergot alkaloidsalkaloids biosynthesis
biosynthesis waswas Floss,
Floss, who, who, in 1976,
in 1976, pre-
presented
sented a seta set
of of information
information ononthe
thesynthesis
synthesisprocesses
processesin inbiological
biological systems.
systems. Since
Since then,
then,
many processes have been clarified and the related knowledge has been expanded [113].
many processes have been clarified and the related knowledge has been expanded [113].
A study by Shu-Ming Li’s team, published in 2014, outlines the biochemical pathways
A study by Shu-Ming Li’s team, published in 2014, outlines the biochemical path-
leading to ergot alkaloids, including lysergic acid [9]. The study collected information
ways leading to ergot alkaloids, including lysergic acid [9]. The study collected infor-
on intermediates, the enzymes used as biocatalysts, and the genes that allowed specific
mation on intermediates, the enzymes used as biocatalysts, and the genes that allowed
reactions to take place. Not all the mechanisms have been confirmed, but the identification
specific reactions to take place. Not all the mechanisms have been confirmed, but the iden-
of intermediates allows for understanding the most likely reaction mechanisms. Similarly,
tification of intermediates allows for understanding the most likely reaction mechanisms.
Mukherjee and Joydeep, in 2000, put together strategies to chemically and biochemically
Similarly, Mukherjee and Joydeep, in 2000, put together strategies to chemically and bio-
synthesize ergot alkaloids [114].
chemically synthesize ergot alkaloids [114].
Lysergic acid biosynthesis begins with L-tryptophan. In the first step, C4-prenylation
Lysergic acid biosynthesis begins with L-tryptophan. In the first step, C4-prenylation
was carried out with the use of an enzyme isolated from Claviceps sp., which is encoded by
was carried out with the use of an enzyme isolated from Claviceps sp., which is encoded
the dmaW gene [115]. For this purpose, the biochemical reaction takes place with dimethy-
by thediphosphate
lallyl dmaW geneas [115]. For this
a prenyl purpose,
donor, in the the biochemical
presence reaction takes placesynthase
of a biocatalyst—DMATS with di-
methylallyl diphosphate as a prenyl donor, in the presence of a biocatalyst—DMATS
prenyltransferase [116]. The mechanism of this reaction, proposed by Metzger, resulted syn-
thase prenyltransferase [116]. The mechanism of this reaction, proposed
from the X-ray structure of the active complex. It includes three stages: formation of the by Metzger, re-
sulted from the
dimethylallyl X-raynucleophilic
cation, structure of attack
the active complex.
of the indole It includes
nucleus to three stages:and
the cation, formation
depro-
tonation [117]. The second step in biosynthesis is N-methylation of allyl-tryptophan and
of the dimethylallyl cation, nucleophilic attack of the indole nucleus to the cation, 224
deprotonation
to the L-abrine[117]. The second
derivative step in biosynthesis
225, catalyzed is N-methylation of
by EasF methyltransferase in allyl-tryptophan
the presence of
224 to the L-abrine derivative
(S)-adenosylmethionine 225, catalyzed
SAM (Scheme by EasF methyltransferase in the presence of
87) [118].
(S)-adenosylmethionine SAM (Scheme 87) [118].
The mechanism of conversion of compound 225 to 228 is not confirmed. It is known
that this reaction requires decarboxylation and oxidation steps using at least two enzymes—
FAD-dependent oxidoreductase (FgaOx1) and FgaCat catalase, in which easE and EasC
genes play a key role. Presumably, this process occurs through the steps of: desatura-
tion of the C8–C9 bond by hydroxylation of the benzyl carbon, deprotonation of the
C17 carbon, oxidation of the C7–C8 bond, and decarboxylation of the epoxide 227 interme-
diate (Scheme 88) [119–122].
methylallyl diphosphate as a prenyl donor, in the presence of a biocatalyst—DMATS syn-
thase prenyltransferase [116]. The mechanism of this reaction, proposed by Metzger, re-
sulted from the X-ray structure of the active complex. It includes three stages: formation
Molecules 2022, 27, x FOR PEER REVIEWof the dimethylallyl cation, nucleophilic attack of the indole nucleus to the cation, 48 ofand
56
deprotonation [117]. The second step in biosynthesis is N-methylation of allyl-tryptophan
Molecules 2022, 27, 7322 Scheme 87. L-abrine
The first stages of lysergic 48 of 56
224 to the derivative 225, acid biosynthesis.
catalyzed by EasF methyltransferase in the presence of
(S)-adenosylmethionine
Scheme 87. The first stages of SAM (Scheme
lysergic 87) [118].
acid biosynthesis.
SchemeThe87.mechanism of conversion
The first stages of compound
of lysergic acid biosynthesis.225 to 228 is not confirmed. It is known
that The
this mechanism
reaction requires decarboxylation
of conversion of compound and 225
oxidation
to 228 issteps using at least
not confirmed. It istwoknownen-
The mechanism of conversion
zymes—FAD-dependent of compound
oxidoreductase (FgaOx1) 225
andtoFgaCat
228 is not confirmed.
catalase, in It iseasE
which known
and
that this reaction requires decarboxylation and oxidation steps using at least two en-
that this
EasC genes reaction requires
play a key role. decarboxylation
Presumably, this and oxidation
process occurs steps using
through at least
theinsteps two
of:easE en-
desatu-
zymes—FAD-dependent oxidoreductase (FgaOx1) and FgaCat catalase, which and
zymes—FAD-dependent
ration of the C8-C9 bond oxidoreductase
by hydroxylation (FgaOx1)
of the and FgaCat
benzyl carbon, catalase, in which
deprotonation of easE
the and
C17
EasC genes play a key role. Presumably, this process occurs through the steps of: desatu-
EasC genes
carbon, play a key therole. Presumably,
bond, and this process occurs through the 227
steps of: desatu-
ration ofoxidation
the C8-C9ofbond C7-C8
by hydroxylation decarboxylation of the
of the benzyl carbon, epoxide
deprotonation intermediate
of the C17
ration of the
(Schemeoxidation C8-C9
88) [119–122]. bond by hydroxylation of the benzyl carbon, deprotonation of the C17
carbon, of the C7-C8 bond, and decarboxylation of the epoxide 227 intermediate
carbon, oxidation of the C7-C8 bond, and decarboxylation of the epoxide 227 intermediate
(Scheme 88) [119–122].
(Scheme
Scheme 87.88)
The[119–122].
first stages of lysergic acid biosynthesis.
Scheme 88. Biomechanism proposed by Metzger.

Scheme 88. Biomechanism proposed by Metzger.
The
Scheme
Scheme next
88.
88. step in theproposed
Biomechanism
Biomechanism synthesis
proposed leads to the aldehyde 229. It is obtained by a short-
byMetzger.
by Metzger.
chainThedehydrogenase/reductase-catalyzed
next step in the synthesis leads toreaction SDR. Wallwey
the aldehyde 229. It is used
obtainedFgaDHby afor this
short-
The
Thenext
purpose next
in thestep
stepininthe
presence synthesis
the
of synthesis
NAD+ leads
[123]. to
leads the aldehyde
to the
Aldehyde aldehyde
229 229.
is an It is It
229. obtained
important by a short-chain
is obtained by a short-
intermediate, from
chain dehydrogenase/reductase-catalyzed reaction SDR. Wallwey used FgaDH for this
dehydrogenase/reductase-catalyzed
chain dehydrogenase/reductase-catalyzed
which compounds suchofasNAD+ reaction
festuclavine, SDR. Wallwey
reaction
pyroclavine, used
SDR. Wallwey FgaDH
usedcanfor this
FgaDH purpose
for this
purpose in the presence [123]. Aldehyde 229 isand agroclavine
an important be obtained
intermediate, from
in the presence
purpose
through in the
the of NAD+of
presence
biochemical [123].
NAD+
pathway Aldehyde
[123].
of 229
Aldehyde
fungi. The isfour-ring
an229
important
is an intermediate,
important
agroclavine from
intermediate,
231 can be which
from
obtained
which compounds such as festuclavine, pyroclavine, and agroclavine can be obtained
compounds
which such
compounds
from Claviceps as festuclavine,
such
purpurea by as pyroclavine,
festuclavine,
treating and
pyroclavine, agroclavine
and can
agroclavinebe obtained
can be through
obtained
through the biochemical pathway ofthe aldehyde
fungi. of the enzyme
The four-ring from231
agroclavine E. festucae var. lolii
can be obtained
the
or biochemical
through
EasG, the
as a pathway
biochemical
result of whichof fungi.
pathway
an ofThe
adduct four-ring
fungi.
withThereduced agroclavine
four-ring 231iscan
agroclavine
glutathione be can
231 obtained
transformed from
be obtained
into the
from Claviceps purpurea by treating the aldehyde of the enzyme from E. festucae var. lolii
Claviceps purpurea
from Claviceps
desired by treating
purpurea
intermediate the
by treating
(Scheme 89)aldehyde of the enzyme from E. festucae var.
the aldehyde of the enzyme from E. festucae var. lolii
[124,125]. lolii or EasG,
or aEasG,
as result asofa result ofanwhich anwith
adduct with reduced glutathione is transformed
into the into the
or EasG, as a which
result of adduct
which an adductreduced
with glutathione is transformed
reduced glutathione is transformed desired
into the
desired intermediate
intermediate (Scheme
(Scheme (Scheme 89)
89) [124,125].[124,125].
desired intermediate 89) [124,125].
Scheme 89. Enzymatic cyclization of the D-ring.

Scheme 89.
Scheme 89. Enzymatic cyclization of
Enzymatic cyclization of the
the D-ring.
D-ring.
The89.
Scheme biosynthesis of lysergic
Enzymatic cyclization ofacid from agroclavine 231 remains unexplained. Among
the D-ring.
the intermediates
The biosynthesis leading to the final
of lysergic acid product, elymoclavine
from agroclavine 232 andunexplained.
remains
231 remains paspalic acidAmong
unexplained. 233 can
The biosynthesis
be distinguished. of lysergic
It is postulated acid
that from agroclavine
cytochrome 231 remains unexplained.
P-450 monooxygenase, or Among
rather its
the intermediates
intermediatesleadingleading totothe
thefinal
finalproduct,
product, elymoclavine
elymoclavine 232232
andand
paspalic acid
paspalic 233 233
acid can
the intermediates
gene—cloA, is an leading
essential to enzyme
the final for
product, elymoclavine
subsequent 232 and
transitions. paspalic acid
Elimoclavin can 233
be can
ob-
be distinguished.
can be distinguished. It isIt postulated
is postulated that
thatcytochrome
cytochromeP-450P-450monooxygenase,
monooxygenase,or or rather
rather its
be distinguished.
tained by the It is postulated thatagroclavin
cytochrome P-450 monooxygenase, or four-elec-
rather its
gene—cloA,
gene—cloA, isistwo-electron
an
anessential oxidation
essentialenzymeenzyme forof subsequent
for subsequent [126]. Then
transitions. the Elimoclavin
application
Elimoclavin
transitions. can of
be
canobtained
be ob-
gene—cloA,
tron
by reduction
the by is
two-electronan
leadsessential
to
oxidation enzyme
paspalic acid for
233
of agroclavin subsequent
[126,127]. transitions.
Paspalic
[126].[126].
ThenThen acid Elimoclavin
can
the applicationbe can
converted be
to ob-
of four-electron ly-
tained the two-electron oxidation of agroclavin the application of four-elec-
tained
sergic
reductionby
acidthe two-electron
either
leadsleads by the
to paspalic oxidation
action of
acid 233 of agroclavin
isomerase or by [126]. Then
spontaneous the application
rearrangements of four-elec-
(Scheme
tron reduction to paspalic acid[126,127]. Paspalic
233 [126,127]. acid can
Paspalic acidbe converted
can to lysergic
be converted to ly-
tron[113].
90)
acid reduction
either by leads
the action to of
paspalic
isomerase acidor233by [126,127].
spontaneous Paspalic acid can be(Scheme
rearrangements converted90) to ly-
[113].
sergic acid either by the action of isomerase or by spontaneous rearrangements (Scheme
sergic acid either by the action of isomerase or by spontaneous rearrangements (Scheme
90) [113].
90) [113].
Scheme 90. Preparation of lysergic acid from agroclavine.

Molecules 2022, 27, 7322 49 of 56
Scheme 90. Preparation of lysergic acid from agroclavine.
Thegenes
The genesforformaking
making ergot
ergot alkaloids
alkaloids are are grouped
grouped together
together in theinproducer’s
the producer’s
genomes.ge-
nomes.
By Bymodification
genetic genetic modification of the host,
of the host, amount theand
amount
type ofand typealkaloids
ergot of ergot produced
alkaloids pro-
can
be varied
duced can[128].
be varied [128].
At
Atthis
thispoint,
point,ititisisworth
worthmentioning
mentioning thethe
publication
publication “Recent progress
“Recent progressin ergot alkaloid
in ergot alka-
research” by Ping
loid research” by Zhu
Ping[129]. In addition
Zhu [129]. to proposing
In addition the mechanisms
to proposing of action
the mechanisms of some
of action of
ergot alkaloids, they presented the characteristics of the key genes and
some ergot alkaloids, they presented the characteristics of the key genes and gene clustersgene clusters
involved
involvedin inthe
thebiosynthetic
biosyntheticprocess
processleading,
leading, inter
inter alia,
alia, to
tolysergic
lysergicacid.
acid. InIn particular,
particular,the
the
focus
focuswas
wason ongenetically
geneticallymodifying
modifying thethestrains,
strains, so
sothat
thatthethemain
mainacid
acidand
anditsitsderivatives
derivatives
can
canbe
beproduced
producedthrough
throughaabiological
biologicalengineering
engineeringstrategy
strategy(Scheme
(Scheme91).91).
Scheme91.
Scheme 91.Lysergic
Lysergicacid
acidbiosynthesis
biosynthesisstrategy
strategyproposed
proposedby
byZhu.
Zhu.
An
Anexemplary
exemplarystrategy
strategyis is to
to start
start the
the biosynthesis
biosynthesis with L-tryptophan 42 and DMAPP. DMAPP.
Next,
Next, inin the modified
modified host host organism,
organism,there therearearetransformations
transformationsfrom from chanoclavine
chanoclavine to to
al-
aldehyde
dehyde 234, andthen
234,and thenthrough
throughagroclavine
agroclavinetotolysergic
lysergicacid
acid[130].
[130].
As
Asmentioned
mentionedatatthe thebeginning,
beginning, thethe
annual
annual production
productionof lysergic acidacid
of lysergic is over 10 tons
is over per
10 tons
year. Chemical total syntheses are characterized by low total yields; therefore,
per year. Chemical total syntheses are characterized by low total yields; therefore, bio- biotechnolog-
ical methods are
technological implemented.
methods In 2022, an analogous
are implemented. In 2022, an biosynthetic
analogouspathway (starting
biosynthetic with
pathway
tryptophan),
(starting withbuttryptophan),
using a modified yeast achassis
but using of the
modified DDM33B
yeast chassisstrain, was
of the used to investigate
DDM33B strain, was
the
usedamount of acid that
to investigate thecould be obtained
amount of acidfrom
that acould
biotechnological
be obtained batch
fromculture. The scale-up
a biotechnological
studies allowedThe
batch culture. for scale-up
estimating that 52
studies g of lysergic
allowed acid can that
for estimating be obtained per yearacid
52 g of lysergic usingcanthe
be
1000 L bioreactor [131].
obtained per year using the 1000 L bioreactor [131].
3. Conclusions
3. Conclusions
Lysergic acid is a very important organic compound that is the common unit of
Lysergic acid is a very important organic compound that is the common unit of ergot
ergot alkaloids. Its intriguing nature has attracted the attention of many research groups.
alkaloids. Its intriguing nature has attracted the attention of many research groups. There-
Therefore, the study of its properties and methods of synthesis has been carried out for
fore, the study of its properties and methods of synthesis has been carried out for many
many decades. In the above work, with the best knowledge of the authors, all known
decades. In the above work, with the best knowledge of the authors, all known chemical
chemical methods of obtaining lysergic acid have been described. Methods leading to
methods of obtaining lysergic acid have been described. Methods leading to its synthesis,
its synthesis, through Woodward, Hendrickson, and Szantay intermediates and Heck
through Woodward, Hendrickson, and Szantay intermediates and Heck coupling meth-
coupling methods, are presented. Other synthetic methods are also summarized, and
ods, are presented.
attempts, although Other syntheticare
unsuccessful, methods are also
described, summarized,
which and attempts,
can be elaborated although
in the future
unsuccessful, are described, which can be elaborated in the future for the
for the preparation of the ergoline system and related derivatives. The biosynthesis of preparation of
the ergoline
lysergic acidsystem
has alsoand related
been derivatives.
described. The biosynthesis
Different approaches, of throughout
lysergic acidthe
has years,
also been
to
lysergic acid have been summarized in Table 2. Lysergic acid does not cease to summa-
described. Different approaches, throughout the years, to lysergic acid have been inspire
rizedgenerations
new in Table 2.ofLysergic acid We
researchers. doesarenot cease
likely to to
seeinspire new generations
novel ideas emerging, soofthis
researchers.
beautiful
We are likely to see novel ideas emerging, so this beautiful molecule
molecule will see solutions to old problems as well as completely new approaches will see solutions to
that are
old problems as
yet to be discovered.well as completely new approaches that are yet to be discovered.
Molecules
Molecules 2022,2022,
27, 27,
7322x FOR PEER REVIEW 50 of 56 50 of 56
Molecules
Molecules 2022,2022,
27, x27,
FORx FOR PEER
PEER REVIEW
REVIEW 50 of
50 56
of 56
Table 2. Summary of chemical methods of obtaining lysergic acid.

Table
2. 2. Summaryofofchemical
chemicalmethods
Table
TableSummary
2. Summary of methods
chemicalof
of obtaining
obtaining
methods lysergic
lysergicacid.
acid.
of obtaining
Optical Ro- lysergic
Yield acid.
[%]
Name of Strategy Year Key Intermediate Optical Ro- Steps * Yield [%] Ref
Name of Strategy Year Key Intermediate tation Ro-Steps *
Optical ** [%] Ref
Yield
Name of Strategy
Woodward strategy Year Key Intermediate tation Steps *
Optical ** ** Ref
Name ofWoodward
Strategy strategy Year Key Intermediate tation Steps * Yield [%] ** Ref
Woodward Woodward
strategy 1956 Rotation
15 0.8 [31]
Julia Woodward
(Baillarge group) 1956
1969 15
11 0.8
- [31]
[47]
Woodward Woodward 1956 15 0.8 [31]
Juliastrategy
(Baillarge
Ramage group) 1969
1976 11
19 -
1.5 [47]
[32]
Julia (Baillarge group) 1969 (±) 11 - [47]
Woodward and Ninomiya1956
KiguchiRamage 1976
1982 (±) 19
20 1.5
0.03 15[32]
[59] 0.8 [31]
Julia (BaillargeRamage
Kiguchi group)
and Ninomiya 1969 1976
1982 (±) 2019 0.031.5 11[59][32] - [47]
Kiguchi andRebek
Ninomiya 1976 1982
1983
(±)
1420 4.40.03 19 [59]
[55,56]
Ramage 1.5 [32]
Rebek 1983 14 4.4 [55,56]
Kiguchi and Ninomiya
Rebek strategy
1982 1983 14 4.4
20 [55,56] 0.03 [59]
Hendrickson
Rebek
Hendrickson strategy
Hendrickson
1983 2004 8 10.6
14 [64]
4.4 [55,56]
Hendrickson
Yigang strategy
Hendrickson
(Snieckus group) 2004
2010 89 10.6
- [64]
[67,69]
Hendrickson
Yigang strategy
(Snieckus group)
Hendrickson 2010
2004 (±) 98 - 10.6 [67,69][64]
Yigang (Snieckus group) 2010 (±) 9 - [67,69]
Hendrickson Beaundry 2004 2020 10(±) - 8 [68] 10.6 [64]
Beaundry 2020 (±) 10 -
Yigang (Snieckus group) 2010 9 [68] - [67,69]
Beaundry
Beaundry
Szantay strategy 2020 2020
-
10 - 10 [68] - [68]
Szantay strategy
Szantay -
2004 15 0.7 [70]
Szantay 2004 15 0.7 [70]
Szantay strategy
Szantay strategy - -
(+)
Szantay
Garner 2004
2021 (+) 15
20(+) 0.210.7 [74][70]
Szantay Garner 2004 2021 20 0.21 15[74] 0.7 [70]
Garner 2021 (+) 20 0.21 [74]
Garner
Closing the C/D-ring 2021 20 0.21 [74]
Closing the C/D-ring
Closing
using the the
HeckC/D-ring
method
using the using
Heckthe method
Heck method
Ortar 1986 (±) 14 2.0 [79]
Ortar theOrtar
Closing C/D-ring 1986 1986 (±) (±)
14 2.0 14[79] 2.0 [79]
Kurihara 1988 (±) 12 1.3 [80,81]
Kurihara
using the Fukuyama
Heck method 1988
Kurihara 1988
2009 (±)
(+) (±)
12
34 1.3
0.9 12
[80,81]
[80] 1.3 [80,81]
Fukuyama Ortar
Fukuyama
Fukuyama 2009 1986
2009
2009 (±)
(+)
(+) 24(+)
3414 0.92.0
0.08 34[80]
[86][79] 0.9 [80]
Fukuyama Fukuyama
Kurihara
Fukuyama 2009 2009
1988
2013 (+)
(±)
(+) 19(+)
2412 0.08
121.3 24[86]
[80,81]
[88] 0.08 [86]
Fukuyama Fukuyama
Fukuyama
Fukuyama 2013 2013
2009
2018 (+)
(+)
(+) 19
30(+)
34 120.9
0.07 19[88]
[91][80] 12 [88]
Fukuyama Fukuyama
Fukuyama
Jia and Liu 2018 2018
2009
2011 (+)
(+)
(+) 30
20(+)
24 0.07
5.10.08 30[91]
[93][86] 0.07 [91]
Jia
Jia and
Jia andFukuyama
Liu and Liu
Liu 2011 2011
2013
2013 (+)
(+)
(+) 20
12(+)
19 5.1
1.012 20[93]
[94][88] 5.1 [93]
JiaOther
Jia andFukuyama
Liu and Liu 2013 2013
2018 (+)
(+) 12(+)
30 1.00.07 12[94][91] 1.0 [94]
Other
Oppolzer 1981 (±) 1720 0.95.1 [85][93]
Jia and Liu 2011 (+)
Other Oppolzer 1981 (±) 17 0.9 [85]
JiaFuji
and and
LiuOhno 2008
2013 (±)
(+) 2112 3.11.0 [98][94]
Oppolzer Fuji
Fuji and
and Ohno
Ohno 1981 2008
2011 (±)
(+) (±)
21
16 3.1
5.9 17[98]
[99] 0.9 [85]
Other
Fuji and Ohno
Fuji
Fuji and
and Ohno
Ohno 2008 2011
2011 (+)
(+) (±)
16
17 5.9
1.8 21[100]
[99] 3.1 [98]
Oppolzer
Fuji and Ohno
1981 (±) 17 0.9 [85]
Fuji and Ohno 2011
* longest linear2011 (+)
sequence from commercially available precursor to 17(+) acid.
lysergic 1.8** where
16[100]
it was 5.9 [99]
Fuji and Ohno *possible,
longest 2008
linear sequence from commercially available (±)
in everyprecursor
21
to lysergic 3.1 [98]
Fuji and Ohno 2011 combined reported yields of reactions step. (+) acid. ** where
17 it was 1.8 [100]
Fuji and Ohno 2011 reported yields of reactions in every step.
possible, combined (+) 16 5.9 [99]
Fuji and Ohno * longest
Author linear sequence
2011
Contributions: from commercially
Conceptualization, available
T.M.W. and M.K.J.; precursor
(+) writing—original
17 to
1.8lysergic
draft acid. ** where it was possible,
[100]
preparation,
combined
Author
M.K.J.;
* longest linear reported
Contributions:
writing—review
sequence yields
from of reactions
Conceptualization,
and editing, T.M.W.
commercially inA.A.K.;
T.M.W.
and every
available step.writing—original
and M.K.J.;
supervision,
precursor to T.M.W. draft
lysergicand preparation,
A.A.K.;
acid. ** funding
where it was
M.K.J.; writing—review
acquisition, T.M.W. and and editing,
A.A.K. T.M.W. have
Allofauthors and A.A.K.; supervision, T.M.W. and A.A.K.; funding
possible, combined reported yields reactions inread
everyand agreed to the
step. published version of the
acquisition,
manuscript. T.M.W. and A.A.K. All authors have read and agreed to the published version of the
Author Contributions: Conceptualization, T.M.W. and M.K.J.; writing—original draft preparation,
manuscript.
Author Contributions:
Funding:
M.K.J.; This workConceptualization,
was funded
writing—review T.M.W.
andbyediting, and
the Narodowe M.K.J.;
T.M.W. writing—original
Centrum
and draftSonata
Nauki, supervision,
A.A.K.; grant preparation,
16
T.M.W. and A.A.K.; funding
Funding:
M.K.J.; This work(to
writing—review
2020/39/D/NZ7/00572 was
and funded
editing,
T.M.W.), and by the
T.M.W. andNarodowe
statutory A.A.K.;
funds from Centrum
MedicalNauki,
supervision,
the T.M.W. grant Sonatafunding
andofA.A.K.;
University Lublin, 16
pro-
acquisition,
2020/39/D/NZ7/00572
ject number
acquisition, T.M.W.
T.M.W.
DS33. and(toA.A.K.and
T.M.W.), A.A.K.
Alland
All
statutory
authors have
authors
funds
readfrom
andthe
have read
Medical
agreed
and
University
to the
agreed
published
to
of Lublin, the
versionpro-
published version of the
of the
manuscript.
ject number
manuscript. DS33.
Institutional Review Board Statement: Not applicable.
Institutional
Funding: ThisReview
work Board
was Statement:
funded Notthe
by applicable.
Narodowe Centrum Nauki,Nauki,
grant grant
SonataSonata
16
Funding:
Informed This
Consent work
Statement: was
Not funded
applicable.by the Narodowe Centrum 16 2020/39/D/NZ7/
2020/39/D/NZ7/00572 (to T.M.W.),
Informed Consent Statement: Notand statutory funds from the Medical University of Lublin, pro-
applicable.
00572 (to T.M.W.), and statutory funds from the Medical University of Lublin, project number DS33.
ject number DS33.
Institutional
Institutional Review Review Board Not
Board Statement: applicable.Not
Statement: applicable.
Informed ConsentConsent
Informed Statement: Not applicable.
Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or
in the decision to publish the results.
Molecules 2022, 27, 7322 51 of 56
Abbreviations
Ac acetyl
AlBN azobisisobutyronitrile
Alloc allyloxycarbonyl
Aq aqueous
BC before Christ
Bn benzyl
Boc tert-Butyloxycarbonyl
Bz benzoyl
◦C degree Celsius
Cat. catalyst
Cbz benzyloxycarbonyl
Cp cyclopentadienyl
CSA camphorsulfonic acid
Cy cyclohexane
DAPCO 1,4-diazabicyclo[2.2.2]octane
DBU 1,8-diazabicyclo(5.4.0)undec-7-ene
DCE 1,2-dichloroethane
DCM dichloromethane or methylene chloride
DEAD diethyl azodicarboxylate
DEPC diethyl pyrocarbonate
DIAD diisopropyl azodicarboxylate
DIBAL-H diisobutylaluminium hydride
DMAP 4-Dimethylaminopyridine (less frequently used for 4-Dimethylaminophenol)
DMAPP dimethylallyl pyrophosphate
DMATS dimethylallyl tryptophan synthase
DMF dimethylformamide
DMSO dimethyl sulfoxide
E. coli lat. Escherichia coli
EAS 5-epi-aristolochene synthase
e.g. lat. exempli gratia, for example
Et ethyl
Fmoc fluorenylmethoxycarbonyl
Fr. short name of discoverer (botanist) Elias Magnus Fries
Grubbs II second-generation Grubbs catalyst
GSH glutathione
HMPA Hexamethylphosphoramide
hν quantum of electromagnetic radiation
IBX 2-Iodoxybenzoic acid
Im imidazole
IPNBSH N-Isopropylidene-N0 -2-nitrobenzenesulfonyl hydrazine
iPr isopropyl
HMDS bis(trimethylsilyl)amide
Lat. from Latin
LDA lithium diisopropylamide
LSD lysergic acid diethylamide
LTMP lithium 2,2,6,6-tetramethylpiperidide
MDM trisiloxane, octamethyl-
Me methyl
MRSA methicyllin-resistant Staphylococcus aureus
Ms mesylate
NAD+/NADH nicotinamide adenine dinucleotide (oxidized and reduced forms)
nBu n-Buthyl
NCS N-Chlorosuccinimide
NiRaney Raney catalyst
NIS N-Iodosuccinimide
Molecules 2022, 27, 7322 52 of 56
NMO N-Methylmorpholine N-oxide

NMP N-Methyl-2-pyrrolidone
Ns (pNs) nosyl, 4-Nitrobenzenesulfonyl
cytochrome, superfamily of enzymes containing heme that functions
P-450
as monooxygenases
Pfb perfluorobutane
PG protecting group
Ph phenyl
Piv pivalic
PNB p-nitrobenzyl
PS (lipase) Pseudomonas
PTSA p-Toluenesulfonic acid, TsOH
Py/Pyr pyridine
R any functional group/further part of molecules
rt room temperature
SAM S-adenosyl methionine
SDR short-chain dehydrogenases/reductases
Sia 1,2-dimethylpropyl
TBAF tetra-n-butylammonium fluoride
TBDMS tert-Butyldimethylsilyl
TBHP tert-Butyl hydroperoxide
tBu tert-butyl
TEMPO 2,2,6,6-Tetramethylpiperidine 1-oxyl
Tf triflate
TFA trifluoroacetic acid
TFE trifluoroethyl alcohol
THF tetrahydrofuran
TIPS triisopropylsilane
TMS tetramethylsilane
TosMIC toluenesulfonylmethyl isocyanide
Ts tosyl, toluenesulfonyl
Tul. short name of discoverer (botanist) Louis Rene Edmond Tulasne
USA United States of America
Var. lat. Varietas, variety
∆ gr. Delta, rise of temperature
µ mikro (prefix)
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Methods of Lysergic Acid Synthesis-The Key Ergot Alkaloid

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Methods of Lysergic Acid Synthesis-The Key Ergot Alkaloid

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molecules

Keywords: lysergic acid; ergot alkaloids; total synthesis; biosynthesis

1. Lysergic Acid as a Component of Ergot Alkaloids

Molecules 2022, 27, 7322. https://doi.org/10.3390/molecules27217322 https://www.mdpi.com/journal/molecules

1.2. Ergot Alkaloids

Figure 1. Structure of ergoline.

Figure 3. Structural formulas of endogenous amines and lysergic acid.

In medicine, ergotamine, dihydroergotamine, dihydroergotoxin, and dihydroer-

Table 1. Activity profile of ergot alkaloids—lysergic acid derivatives.

1.3. Lysergic Acid

History of Lysergic Acid [24]

Scheme 2. Obtaining Uhle’s ketone 8.

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Optimization studies were performed according to Price and Krishnamurti, which

lysergic acid 1 can be obtained from it by hydrolysis and dehydrogenation.

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Scheme 13. Second part of the Ramage synthesis.

This work is an interesting attempt to obtain an optically pure intermediate. The

Scheme 21. The last part of Kiguchi synthesis.

Scheme 23. A new method for the synthesis of compound 51.

Scheme 25. Obtaining Hendickson’s intermediate.

Scheme 25. Obtaining Hendickson’s intermediate.

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2.2.2. Problems Noticed by Bekkam

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Scheme 33. Preparation

Scheme 34. Obtaining Szantay’s intermediate.

Figure 12. Structural

2.4.1. Ortar and Kurihara Groups

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Scheme 44. Protection of the tetrahydropyridine with a nosyl group.

Subsequent reactions involved the deprotection and methylation of tetrahydro-

Scheme 46. Preparation of ester 120.

Acetate 124 was

Molecules 2022, 27, x FOR PEER REVIEW Strategy III. Another

Scheme 55. Preparation of the hemiaminal 136.

hemiaminal 136 (Scheme 55).

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Scheme 61. Synthesis

Scheme 62. Closing the D-ring in Fukuyama strategy IV.

2.4.3. Liu and Jia Research

Scheme 74. Enolate ether 192 synthesis.

Scheme 75. Obtaining allene in strategy I.

The preparation of the tetracyclic ergoline structure was accomplished by palladium-

Strategy II.II. The allene

Commercially available 4-bromoindole 61 was formylated by the Vilsmeier–Haack

Scheme 81. Synthesis of enyne 210 from bromoindole.

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Scheme 83. Retrosynthetic analysis proposed by Padwa.

Scheme 88. Biomechanism proposed by Metzger.

Scheme 89. Enzymatic cyclization of the D-ring.

Scheme 90. Preparation of lysergic acid from agroclavine.

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Scheme 90. Preparation of lysergic acid from agroclavine.

Table 2. Summary of chemical methods of obtaining lysergic acid.

NMO N-Methylmorpholine N-oxide

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