Strychnine (/strknin/; also US /strknan/ or /strknn/) is a highly toxic (LD50 = 0.

16 mg/kg in rats, 1
2 mg/kg orally in humans[2]), colorless, bitter crystalline alkaloid used as a pesticide, particularly for killing
small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed or absorbed through
eyes or mouth, causes a poisoning which results in muscular convulsions and eventually death
through asphyxia.[3] The most common source is from the seeds of the Strychnos nux-vomica tree.

History[edit]
Strychnine was the first alkaloid to be identified in plants of the genus Strychnos,
family Loganiaceae. Strychnos, named by Carl Linnaeus in 1753, is a genus of trees and climbing shrubs of
the gentian order. The genus contains 196 various species and is distributed throughout the warm regions
of Asia (58 species), America (64 species), and Africa (75 species). The seeds and bark of many plants in
this genus contain the powerful poison strychnine.
The toxic and medicinal effects of Strychnos nux-vomica have been well known from the times of ancient
India, although the chemical compound itself was not identified and characterized until the 19th century. The
inhabitants of these countries had historical knowledge of the species Strychnos nux-vomica and SaintIgnatius bean (Strychnos ignatii). Strychnos nux-vomica is a tree native to the tropical forests on the
Malabar Coast in Southern India, Srilanka and Indonesia, which attains a height of about 12 m. The tree has
a crooked, short, thick trunk and the wood is close grained and very durable. The fruit has an orange color
and is about the size of a large apple with a hard rind and contains five seeds, which are covered with a soft
wool-like substance. The ripe seeds look like flattened disks, which are very hard. These seeds are the chief
commercial source of strychnine and were first imported to and marketed in Europe as a poison to kill
rodents and small predators. Strychnos ignatii is a woody climbing shrub of the Philippines. The fruit of the
plant, known as Saint Ignatius' bean, contains as many as 25 seeds embedded in the pulp. The seeds
contain more strychnine than other commercial alkaloids. The properties of S. nux-vomica and S. ignatii are
substantially those of the alkaloid strychnine.
Strychnine was first discovered by French chemists Joseph Bienaim Caventou and Pierre-Joseph
Pelletier in 1818 in the Saint-Ignatius bean.[4] In some Strychnos plants a 9,10-dimethoxy derivative of
strychnine, the alkaloid brucine, is also present. Brucine is not as poisonous as strychnine. Historic records
indicate that preparations containing strychnine (presumably) had been used to kill dogs, cats, and birds in
Europe as far back as 1640[citation needed]. The structure of strychnine was first determined in 1946 by SirRobert
Robinson and in 1954 this alkaloid was synthesized in a laboratory by Robert B. Woodward. This is one of
the most famous syntheses in the history of organic chemistry. Both chemists won the Nobel
prize (Robinson in 1947 and Woodward in 1965).[5]

Biosynthesis

Strychnine is a terpene indole alkaloid belonging to the Strychnos family of Corynanthe alkaloids, and it is
derived from tryptamine and secologanin.[6][7] The enzyme, strictosidine synthase, catalyzes the
condensation of tryptamine and secologanin, followed by a Pictet-Spengler reaction to form strictosidine.
[8]

While the enzymes that catalyze the following steps have not been identified, the steps have been inferred

by isolation of intermediates from Strychnos nux vomica.[9] The next step is hydrolysis of the acetal, which
opens the ring by elimination of glucose(O-Glu) and provides a reactive aldehyde. The nascent aldehyde is
then attacked by a secondary amine to afford geissoschizine, a common intermediate of many related
compounds in the Strychnos family.[6]
A reverse Pictet-Spengler reaction cleaves the C2-C3 bond, while a subsequent Mannich reaction forms the
C3-C7 bond, and a Michael addition forms the C2-C16 bond to provide dehydropreakuammicine. Hydrolysis
of the methyl ester and decarboxylation leads tonorfluorocurarine. Stereospecific reduction of the endocyclic
double bond by NADPH and hydroxylation provides the Wieland-Gumlich aldehyde, which was first isolated

by Heimberger and Scott in 1973, although previously synthesized by Wieland and Gumlich in 1932. [9][10] To
elongate the appendage by 2 carbons, acetyl-CoA is added to the aldehyde in analdol reaction to afford
prestrychnine. Strychnine is then formed by a facile addition of the amine with the carboxylic acid or its
activated CoAthioester, followed by ring-closure via displacement of an activated alcohol.

Chemical synthesis[edit]
Main article: Strychnine total synthesis
As early researchers have noted, the strychnine molecular structure, with its specific array of rings,
stereocenters, and nitrogen functional groups is a complex synthetic target, and has stimulated interest for
that reason and for interest in the structure-activity relationships underlying its pharmacologic activities.[11] An
early synthetic chemist targeting strychnine, R.B. Woodward, quoted the chemist who determined its
structure through chemical decomposition and related physical studies as saying that "for its molecular size
it is the most complex [organic] substance known" (attributed to Sir Robert Robinson).[12]
The first total synthesis of strychnine was reported by the research group of R.B. Woodward in 1954, and is
considered a classic in this field.[13][page needed][14] The Woodward account published in 1954 was very brief (3 pp.),
[15]

but was followed by a 42 page report in 1963.[16] The molecule has since received continuing wide

attention in the years since for the challenges to synthetic organic strategy and tactics presented by its
complexity; its synthesis has been targeted and its stereocontrolled preparation independently achieved by
more than a dozen research groups since the first success (see main strychnine total synthesis article).

ADME[edit]
This section needs additional citations for verification. Please help improve this
article by adding citations to reliable sources. Unsourced material may be challenged and
removed. (June 2014)

Absorption[edit]
Strychnine may be introduced into the body orally, by inhalation, or by injection. It is a potently bitter
substance, and in humans has been shown to activate bitter taste receptorsTAS2R10 and TAS2R46.[17][18]
[19]

Strychnine is rapidly absorbed from the gastrointestinal tract. [citation needed]

Distribution[edit]
Strychnine is transported by plasma and erythrocytes. Due to slight protein binding, strychnine leaves the
bloodstream quickly and distributes to the tissues. Approximately 50% of the ingested dose can enter the
tissues in 5 minutes. Also within a few minutes of ingestion, strychnine can be detected in the urine. Little
difference was noted between oral and intramuscular administration of strychnine. [citation needed] In persons killed
by strychnine, the highest concentrations are found in the blood, liver, kidney and stomach wall. The usual

fatal dose is 60100 mg strychnine and is fatal after a period of 12 hours, though lethal doses vary
depending on the individual.

Metabolism[edit]
Strychnine is rapidly metabolized by the liver microsomal enzyme system requiring NADPH and O2.
Strychnine competes with the inhibitory neurotransmitter glycine resulting in an excitatory state. However,
the toxicokinetics after overdose have not been well described. In most severe cases of strychnine
poisoning, the patient dies before reaching the hospital. The biological half-life of strychnine is about 10
hours. This half-life suggests that normal hepatic function can efficiently degrade strychnine even when the
quantity ingested is high enough to cause severe poisoning.

Excretion[edit]
A few minutes after ingestion, strychnine is excreted unchanged in the urine, and accounts for about 5 to
15% of a sublethal dose given over 6 hours. Approximately 10 to 20% of the dose will be excreted
unchanged in the urine in the first 24 hours. The percentage excreted decreases with the increasing dose.
Of the amount excreted by the kidneys, about 70% is excreted in the first 6 hours, and almost 90% in the
first 24 hours. Excretion is almost complete in 48 to 72 hours.[5]

Mechanism of action[edit]
Strychnine is a neurotoxin which acts as an antagonist of glycine and acetylcholine receptors. It primarily
affects the motor nerves in the spinal cord which control muscle contraction. An impulse is triggered at one
end of a nerve by the binding of neurotransmitters to the receptors. In the presence of a neuroinhibitor, such
as glycine, a greater quantity of excitatory neurotransmitters must bind to receptors before there will be an
action potential generated. Glycine acts primarily as an agonist of the glycine receptor, which is a ligandgated chloride channel in neurons located in the spinal cord and in the brain. This chloride channel will allow
the negatively charged chloride ions into the neuron, causing a hyperpolarization which pushes the
membrane potential further from threshold. Strychnine is an antagonist of glycine, which means it binds to
the same receptor, preventing the inhibitory effects of glycine on the postsynaptic neuron. Therefore, action
potentials are triggered with lower levels of excitatory neurotransmitters. When the inhibitory signals are
prevented, the motor neurons do will be more easliy activated and the victim will have spastic muscle
contractions.[20] Structure of strychnine in complex with ACh binding protein (AChBP).[21]
Strychnine is also an antagonist for acetylcholine receptors,[22] which is known to be homologous to the
glycine receptor.

Toxicity[edit]
This section needs additional citations for verification. Please help improve this
article by adding citations to reliable sources. Unsourced material may be challenged and

removed. (June 2014)

Strychnine is very toxic to humans and many other animals, and poisoning by inhalation, swallowing or
absorption through eyes or mouth can be fatal.[citation needed] S. nux-vomicaseeds are generally effective only
when they are crushed or chewed before swallowing because the pericarp is quite hard and indigestible;
poisoning symptoms may therefore not appear if the seeds are ingested whole. [citation needed]

Animal toxicity[edit]
This section does not cite any references or sources. Please help improve this section
by adding citations to reliable sources. Unsourced material may be challenged
and removed. (June 2014)

Strychnine poisoning in animals usually occurs from ingestion of baits designed for use against gophers,
moles and coyotes. Strychnine is also used as a rodenticide, but is not specific for such unwanted pests
and may kill other small animals. In the United States, most baits containing strychnine have been replaced
with zinc phosphide baits since 1990. In the Netherlands rodenticides with strychnine are forbidden.
Strychnine toxicity in rats is dependent on sex. It is more toxic to females than to males when administered
via subcutaneous injection or intraperitoneal injection. Differences are due to higher rates of metabolism by
male rat liver microsomes. Dogs and cats are more susceptible among domestic animals, pigs are believed
to be as susceptible as dogs, and horses are able to tolerate relatively large amounts of strychnine. Birds
affected by strychnine poisoning exhibit wing droop, salivation, tremors, muscle tenseness andconvulsions.
Death occurs as a result of respiratory arrest. The clinical signs of strychnine poisoning relate to its effects
on the central nervous system. The first clinical signs of poisoning include nervousness, restlessness,
twitching of the muscles, and stiffness of the neck. As the poisoning progresses, the muscular twitching
becomes more pronounced and convulsions suddenly appear in all the skeletal muscles. The limbs are
extended and the neck is curved to opisthotonus. The pupils are widely dilated. As death approaches, the
convulsions follow one another with increased rapidity, severity, and duration. Death results from asphyxia
due to prolonged paralysis of the respiratory muscles. Following the ingestion of strychnine, symptoms of
poisoning usually appear within 15 to 60 min. The LD50-values for strychnine in animals are listed below in
table 1.

The LD50 values for strychnine in animals

Organism

Bird-wild[23]

Route

Oral

LD50 (mg/kg)

16

Cat[24]

Intravenous

0.33

Cat[25]

Oral

0.5

Dog[26]

Intravenous

0.8

Dog[24]

Subcutaneous

0.35

Dog[25]

Oral

0.5

Duck[23]

Oral

3.0

Mouse[27]

Intraperitoneal

0.98

Mouse[28]

Intravenous

0.41

Mouse[29]

Oral

2.0

Mouse[30]

Parenteral

1.06

Mouse[31]

Subcutaneous

0.47

Pigeon[23]

Oral

21.0

Quail[23]

Oral

23.0

Rabbit[26]

Intravenous

0.4

Rabbit[24]

Oral

0.6

Rat[32]

Oral

16.0

Rat[33]

Oral

2.35

Human toxicity[edit]
The symptoms of poisoning in humans are generally similar to those as in other animals, because the
mechanism of action is apparently similar across species. The toxicity of strychnine in humans is not
ethically studied, so most information known comes from cases of strychnine poisoning, unintentional and
deliberate.
The following symptoms are indicative of a lethal dose:
1. Severe nausea, including vomiting
2. Convulsions of all muscle groups, which become longer and more closely spaced with time
3. Spasms of the facial muscles, causing cyanosis of the face, dilated pupils, prominent eyeballs, and
frothing at the mouth
4. The body may exhibit the following "arching"/"bridging" postures:
1. Opisthotonus: Hymperextension. The person may be resting on heels and occiput.
2. Emprosthotonos: The spasm of abdominal muscles may bend the body forward.
3. Pleurothotonus: The body may be flexed to one side.
5. Loss of consciousness and a clear mind
6. Immense reflex sensitivity (dramatic exaggeration of normal reflexes)
7. Death due to asphyxiation, caused by muscle spasms[3]
The LD50-values estimated from different cases of strychnine poisoning are listed below in table 2.

The LD50 values for strychnine in humans

Route

LD50 (mg)

Human[34][35]

Oral

100120

Human[36]

Oral

3060

Human (child)[37][38][39]

Oral

15

Human (adult)[40]

Oral

50100

Human (adult)[39]

Oral

30100

Human (adult)[38]

Oral

30

Human[41]

Intravenously

510 (approximate)

For occupational exposures to strychnine, the Occupational Safety and Health Administration and National
Institute for Occupational Safety and Health have set exposure limits at 0.15 mg/m3 over an 8-hour work
day.[42]
Because strychnine produces some of the most dramatic and painful symptoms of any known toxic
reaction, strychnine poisoning is often portrayed in literature and film. [citation needed]

Treatment[edit]

[hide]This section has multiple issues. Please help improve it or discuss these iss
page.
This section does not cite any references or sources.
This section's factual accuracy is disputed.

(June 2014)

(June 2014)

There is no specific antidote for strychnine but recovery from strychnine exposure is possible with early
hospital treatment. Treatment consists of removing the drug from the body (decontamination) and getting
supportive medical care in a hospital setting. Supportive care includes intravenous fluids, medications

against convulsions and spasms, and cooling measures for high temperature. The patient should be kept in
a quiet and darkened room, because excessive manipulation and loud noises may cause convulsions.
Because these convulsions are extremely painful, an appropriate painkiller should be given. Treatment of
strychnine poisoning involves an oral administration of activated charcoal which adsorbs any strychnine
within the digestive tract. Unabsorbed strychnine can be removed from the stomach by gastric
lavage with tannic acid or potassium permanganate solutions to oxidize strychnine. Seizures are controlled
by anticonvulsants, such as phenobarbital or diazepam, along with muscle relaxants such as dantrolene to
combat muscle rigidity. Chloroform or heavy doses of chloral, bromide, urethane or amyl nitrate can also be
used to restrain the convulsions. Because diazepam, as the anticonvulsant of choice, is not effective in all
cases, a combination with midazolam, fentanyl, or pancuronium is recommended for controlling the
convulsions. Strychnine poisoning demands an aggressive management with early intubation, control of
muscle tremors, and prevention of rhabdomyolysis and renal failure. If the patient survives the first 24 hours
after poisoning then recovery is probable. Also, George Harley (18291896) showed in 1850
that Curare (wourali) was effective for the treatment of tetanus and strychnine poisoning.

Strychnine total synthesis in chemistry describes the total synthesis of the

complex biomolecule strychnine. The first reported method by the group of Robert Burns Woodward in 1954
is considered a classic in this research field.[2][3][4] [5]
At the time it formed the natural conclusion to an elaborate process of molecular structure elucidation that
started with the isolation of strychnine from the beans of Strychnos ignatii by Pierre Joseph
Pelletier and Joseph Bienaim Caventou in 1818.[6] Major contributors to the entire effort were Sir Robert
Robinson with over 250 publications and Hermann Leuchs with another 125 papers in a time span of 40
years. Robinson was awarded the Nobel Prize in Chemistry in 1947 for his work on alkaloids, strychnine
included.
The process of chemical identification was completed with publications in 1946 by Robinson

[7][8][9]

and later

confirmed by Woodward in 1947.[10] X-ray structures establishing the absolute configuration became
available between 1947 and 1951 with publications from J. M. Bijvoet [11][12] and J.H. Robertson [13] .[14]
Woodward published a very brief account on the strychnine synthesis in 1954 (just 3 pages)

[15]

and a

lengthy one (42 pages) in 1963.[16]

Many more methods exist and reported by the research groups of Magnus, [17] Overman,[18] Kuehne,[19]
[20]

Rawal,[21] Bosch,[22][23] Vollhardt,[24][25] Mori,[26][27] Shibasaki,[28] Li,[29]Fukuyama [30] Vanderwal [31] and MacMillan.

[32]

Synthetic (+)-strychnine is also known.[33][34] Racemic synthesises were published by Padwa in 2007 [35] and

in 2010 by Andrade[36] and by Reissig.[37] In his 1963 publication Woodward quoted Sir Robert Robinson who
said [38] for its molecular size it is the most complex substance known.

The molecule[edit]

The C21H22N2O2 strychnine molecule contains 7 rings including an indoline system. It has a tertiary
amine group, an amide, an alkene and an ether group. The naturally occurring compound is
also chiral with 6 asymmetric carbon atoms including one quaternary one.

Woodward synthesis[edit]
Ring II, V synthesis[edit]
The synthesis of ring II was accomplished with an Fischer indole
synthesis using phenylhydrazine 1 and acetophenone derivative
acetoveratrone 2 (catalyst polyphosphoric acid) to give the 2-veratrylindole 3. The veratryl group not
only blocks the 2-position for further electrophilic substitution but will also become part of the
strychnine skeleton. A Mannich reaction with formaldehyde and dimethylamine)
produced gramine 4. Alkylation with iodomethane gave an intermediate quaternary ammonium
salt which reacted with sodium cyanide in a nucleophilic substitution to cyanide 5 and then in
a reduction with lithium aluminium hydride to tryptamine 6. Amine-carbonyl condensation with ethyl
glyoxylate give the imine 7. The reaction of this imine with TsCl in pyridine to the ring-closed N-tosyl
compound 8 was described by Woodward as a concerted nucleophilic enamine attack and formally

a PictetSpengler reaction. This compound should form as a diastereomeric pair but only one
compound was found although which one was not investigated. Finally the newly formed double
bond was reduced by sodium borohydride to indoline 9 with the C8 hydrogen atom approaching
from the least hindered side (this proton is destroyed later on in the sequence and of no
importance).

Ring III, IV synthesis[edit]

Indoline 9 was acetylated to N-acetyl compound 10 (acetic anhydride, pyridine) and then the
veratryl group was then ring-opened with ozone in aquaeous acetic acid to muconic
ester 11 (made possible by the two electron-donating methoxide groups). This is an example
of bioinspired synthesis already proposed by Woodward in 1948.[39] Cleavage of the acetyl

group and ester hydrolysis with HCl in methanol resulted in formation of pyridone ester 12 with
additional isomerization of the exocyclic double bond to an endocyclic double bond (destroying
one asymmetric center). Subsequent treatment with hydrogen iodide and red
phosphorus removed the tosyl group and hydrolysed both remaining ester groups to
form diacid 13. Acetylation and esterfication (diazomethane) produced acetyl diester 14 which
was then subjected to a Dieckman condensation with sodium methoxidein methanol to enol 15.

Ring VII synthesis[edit]

In order to remove the C15 alcohol group, Enol 15 was converted
to tosylate 16 (TsCl, pyridine) and then to mercaptoester 17 (sodium benzylmercaptide)
which was then reduced to unsaturated ester 18 by Raney nickel and hydrogen. Further
reduction with hydrogen / palladium on carbon afforded the saturated ester 19. Alkaline
ester hydrolysis to carboxylic acid 20 was accompanied by epimerization at C14.

This particular compound was already known from strychnine degration studies. Until now all
intermediates were racemic but chirality was introduced at this particular stage viachiral
resolution using quinidine.
The C20 carbon atom was then introduced by acetic anhydride to form enol acetate 21 and the free
aminoketone 22 was obtained by hydrolysis with hydrochloric acid. Ring VII in intermediate 23 was closed
by selenium dioxide oxidation, a process accompanied by epimerization again at C14.

The formation of 21 can be envisioned as a sequence of acylation, deprotonation, rearrangement with loss
of carbon dioxide and again acylation:

Ring VI synthesis[edit]
To diketone 23 was added sodium acetylide (bringing in carbon atoms 22 and 23) to give alkyne 24. This
compound was reduced to the allyl alcohol 25 using the Lindlar catalystand lithium aluminium
hydride removed the remaining ketone group in 26. An allylic rearrangement to alcohol 27 (isostrychnine)
was brought about by hydrogen bromide in acetic acid followed by hydrolysis with sulfuric acid. In the final
step to (-)-strychnine 28 treatment of 27 with ethanolic potassium hydroxide caused rearrangement of the
C12-13 double bond and ring closure in a conjugate addition by the hydroxyl anion.

Magnus synthesis[edit]
In this effort one of strychnine's many degradation products was synthesised first (the relay compound), a
compound also available in several steps from another degradation product called the Wieland-Gumlich
aldehyde. In the final leg strychnine itself was synthesised from the relay compound.

Overman synthesis[edit]
The Overman synthesis (1993) took a chiral cyclopentene compound as starting material obtained by
enzymatic hydrolysis of cis-1,4-diacetoxycyclopent-2-ene. This starting material was converted in several
steps to trialkylstannane 2 which was then coupled with an aryl iodide 1 in a Stille reaction in presence
of carbon monoxide(tris(dibenzylideneacetone)dipalladium(0), triphenylarsine). The internal double in 3 was
converted to an epoxide using tert-Butyl hydroperoxide, the carbonyl group was then converted to
an alkene in a Wittig reaction using Ph3P=CH2 and the TIPS group was hydrolyzed (TBAF) and replaced by
a trifluoroacetamide group (NH2COCF3, NaH) in 4.Cyclization (NaH) took place next, opening the epoxide
ring and the trifluoroacetyl group was removed using KOH affording azabicyclooctane 5.

The key step was an aza-Cope Mannich reaction initiated by an amine-carbonyl

condensation using formaldehyde and forming 6 in a quantitative yield:

In the final sequence strychnine was obtained through the Wieland-Gumlich aldehyde (10):

Intermediate 6 was acylated using methyl cyanoformate and two protective groups (tert-butyl and ) were
removed using HCl / MeOH in 7. The C8C13 double bond was reduced with zinc (MeOH/H+) to saturated
ester 8 (mixture). Epimerization at C13 with sodium methoxide in MeOH produced beta-ester 9 which was
reduced with [[diisobutylaluminium hydride ]] to Wieland-Gumlich aldehyde 10. Conversion of this
compound with malonic acid to (-)-strychnine 11 was already known as a procedure.

Kuehne synthesis[edit]
The 1993 Keuhne synthesis concerns racemic strychnine. Starting compounds tryptamine 1 and 4,4dimethoxy acrolein 2 were reacted together with boron trifluoride to acetal 3as a single diastereomer in
an amine-carbonyl condensation / sigmatropic rearrangement sequence.

Hydrolysis with perchloric acid afforded aldehyde 4. A Johnson-Corey-Chaykovsky

reaction (trimethylsulfonium iodide / n-butyllithium) converted the aldehyde into an epoxidewhich reacted
in situ with the tertiary amine to ammonium salt 5 (contaminated with other cyclization products).
Reduction (palladium on carbon/hydrogen) removed the benzylgroup to alcohol 6, more reduction (sodium
cyanoborohydride) and acylation (acetic anhydride / pyridine) produced 7 as a mixture of epimers (at
C17). Ring closure of ring III to 8was then accomplished with an aldol reaction using lithium
bis(trimethylsilyl)amide (using only the epimer with correct configuration). Even more reduction (sodium
borohydride) and acylation resulted in epimeric di-acetate 9.

A DBU mediated elimination reaction formed olefinic alcohol 10 and subsequent Swern oxidation have an
unstable amino ketone 11. In the final steps a HornerWadsworthEmmons reaction (methyl 2(diethy1phosphono)acetate) give acrylate ester 12 as a mixture of cis and trans isomers which could be
coached into the right (trans) direction by application of light in a photochemical rearrangement, the ester
group was reduced (DIBAL / boron trifluoride) to isostrychnine 13 and racemic strychnine 14 was formed by
base-catalyzed ring closure as in the Woodward synthesis.

In the 1998 Keuhne synthesis of chiral (-)-strychnine the starting material was derived from
chiral tryptophan.

Rawal synthesis[edit]
In the Rawal synthesis (1994, racemic) amine 1 and enone 2 were combined in an amine-carbonyl
condensation followed by methyl chloroformate quench to triene 3 which was then reacted in a Diels-Alder
reaction (benzene 185C) to hexene 4. The three ester groups were hydrolyzed
using iodotrimethylsilane forming pentacyclic lactam 5 after a methanol quench in a combination of 7
reaction steps (one of them a Dieckmann condensation). The C4 segment 6 was added in an amine
alkylation and Heck reaction of 7formed isostrychnine 8 after TBS deprotection.

The overall yield (10%) is to date the largest of any of the published methods

[40]

Bosch synthesis[edit]
In the Bosch synthesis of (1999, chiral) the olefin group in dione 1 was converted to
an aldehyde by ozonolysis and chiral amine 2 was formed in a double reductive aminationwith (S)-1phenylethylamine. The phenylethyl substituent was removed using ClCO2CHClCH3 and the enone group
was introduced in a Grieco elimination using TMSI, HMDSthen PhSeCl then ozone and
then diisopropylamine forming carbamate 3. The amino group was deprotected by refluxing in methanol
and then alkylated using (Z)-BrCH2CICH=CH2OTBDMS, to tertiary amine 4. A reductive Heck reaction took
place next followed by methoxycarbonylation (LiHMDS, NCCO2Me) to tricycle 5. Reaction with zincdust in
10% sulfuric acid removed the TBDMS protective group, reduced the nitro group and brought about a
reductive amino-carbonyl cyclization in a single step to tetracyclic 6(epimeric mixture). In the final step to

the Wieland-Gumlich aldehyde 7 reaction with NaH in MeOH afforded the correct epimer was followed
by DIBAH reduction of the methyl ester.

Vollhardt synthesis[edit]
The key reaction in the Vollhardt synthesis (2000, racemic) was an alkyne
trimerisation of tryptamine derivative 1 with acetylene and organocobalt compound CpCo(C2H4)2 (THF, 0 C)
to tricycle 2 after deprotection of the amine group (KOH, MeOH/H2O reflux). Subsequent reaction with iron
nitrate brought about a [1,8]-conjugate addition to tetracycle 3,amine alkylation with (Z)-1-bromo-4-[(tertbutyldimethylsilyl)oxy]-2-iodobut-2-ene (see Rawal synthesis) and lithium carbonate, and isomerization of
the diene system (NaOiPr, iPrOH) formed enone 4. A Heck reaction as in the Rawal synthesis (palladium
acetate / triphenylphosphine), accompanied by aromatization formed pyridone 5 and lithium aluminium
hydride reduction and TBS group deprotection formed isostrychnine 6.

Mori synthesis[edit]
The Mori synthesis ((-) chiral, 2003) was the first one containing an asymmetric reaction step. It also
features a large number of Pd catalyzed reactions. In it N-tosyl amine 1reacted with allyl carbonate 2 in
an allylic asymmetric substitution using Pd2(dba)3 and asymmetric ligand (S-BINAPO) to chiral secondary
amine 3. Desilylation of the TBDMSgroup next took place by HCl to the hydroxide and then to
the nitrile 4 (NaCN) through the bromide (PBr3). Heck reaction (Pd(OAc)2 / Me2PPh) and debromination
(Ag2CO3) afforded tricycle 5. LiALH4 Nitrile reduction to the amine and its Boc2O protection to boc
amine 6 was then followed by a second allylic oxidation (Pd(OAc)2 / AcOH / benzoquinone/ MnO2) to
tetracycle 7. Hydroboration-oxidation (9-BBN / H2O2) gave alcohol 8 and subsequent Swern
oxidation ketone 9. Reaction with LDA / PhNTf2 gave enol triflate 10 and the triflate group was removed
in alkene 11 by reaction with Pd(OAc)2 and PPh3.

Detosylation of 11 (sodium naphthalenide) and amidation with acid chloride 3-bromoacryloyl chloride gave
amide 12 and another Heck reaction gave pentacycle 13. double bond isomerization (sodium / iPrOH), Boc
group deprotection (triflic acid) and amine alkylation with (Z)-BrCH2CICH=CH2OTBDMS (see Rawal) gave
compound 14 (identical to one of the Vollhardt intermediates). A final heck reaction (15) and TBDMS
deprotection formed (-)-isostrychnine 16.

Shibasaki synthesis[edit]
The Shibasaki synthesis ((-) chiral, 2002) was a second published method in strychnine total synthesis
using an asymmetric reaction step. Cyclohexenone 1 was reacted withdimethyl malonate 2 in
an asymmetric Michael reaction using AlLibis(binaphthoxide) to form chiral diester 3. Its ketone group was
protected as an acetal (2-ethyl-2-methyl-1,3-dioxolane, TsOH) and a carboxyl group was removed
(LiCl, DMSO 140 C) in monoester 4. A C2 fragment was added as Weinreb amide 5 to form PMB
ether 6 using LDA. The ketone was then reduced to the alcohol (NaBH3CN, TiCl4) and then water
was eliminated (DCC, CuCl) to form alkene 7. After ester reduction (DIBAL) to the alcohol and
its TIPSprotection (TIPSOTf, triethylamine), the acetal group was removed (catalytic CSA) in
ketone 8. Enone 9 was then formed by Saegusa oxidation. The conversion to alcohol 10 was accomplished
via a Mukaiyama aldol addition using formaldehyde, iodonation to 11 (iodine, DMAP) was followed by
a Stille coupling (Pd2dba3, Ph3As, CuI) incorporatingnitrobenzene unit 12. Alcohol 13 was formed
after SEM protection (SEMCl,i-Pr2NEt) and TIPS removal (HF).

In the second part of the sequence alcohol 13 was converted to a triflate (Triflic anhydride, N,NDiisopropylethylamine), then 2,2-bis(ethylthio)ethylamine 14 was added immediately followed
by zinc powder, setting of a tandem reaction with nitro group reduction to the amine, 1,4-addition of the thioamine group and amine-keto condensation to indole 16. Reaction with DMTSF gave thionium attack at C7
forming 17, the imine group was then reduced (NaBH3CN, TiCl4), the new amino group acylated (acetic
anhydride,pyridine), both alcohol protecting groups removed (NaOMe / meOH) and the allyl alcohol group
protected again (TIPS). This allowed removal of the ethylthio group (NiCl2,NaBH4, EtOH/MeOH) to 18. The
alcohol was oxidized to the aldehyde using a Parikh-Doering oxidation and TIPS group removal gave
hemiacetal 19 called (+)-diaboline which is acylated Wieland-Gumlich aldehyde.

Li synthesis[edit]
The synthesis reported by Bodwell/Li(racemic, 2002) was a formal synthesis as it produced a compound
already prepared by Rawal (no. 5 in the Rawal synthesis). The key step was an inverse electron demand
Diels-Alder reaction of cyclophane 1 by heating in N,N-diethylaniline (dinitrogen is expulsed) followed by
reduction of double bond in 2 to 3 bysodium borohydride / triflic acid and removal of
the carbamate protecting group (PDC / celite) to 4.

The method is disputed by Reissig (see Reissig synthesis).

Fukuyama synthesis[edit]
The Fukuyama synthesis (chiral (-), 2004) started from cyclic amine 1. Chirality was at some point
introduced into this starting material by enzymatic resolution of one of the precursors. Acyloin 2 was
formed by Rubottom oxidation and hydrolysis. Oxidative cleavage by lead acetate formed aldehyde 3,
removal of the nosyl group (thiophenol / cesium carbonate) triggered an amine-carbonyl
condensation with iminium ion 4 continuing to react in a transannular cyclization to diester 5 which could
be converted to the Wieland-Gumlich aldehyde by known chemistry.

Reissig synthesis[edit]
The method reported by Beemelmanns & Reissig (racemic, 2010) is another formal synthesis leading to the
Rawal pentacycle (see amine 5 in the Rawal method). In this method indole 1 was converted to
tetracycle 2 (together with by-product) in a single cascade reaction using samarium diiodide and HMPA.
[41]

Raney nickel/ H2 reduction gave amine 3and a one-pot reaction using methyl

chloroformate, DMAP and TEA then MsCl, DMAP and TEA and then DBU gave Rawal precursor 4 with key
hydrogen atoms in the desired anti configuration.

In an aborted route intermediate 2 was first reduced to imine 5 then converted to carbamate 6, then
dehydrated to diene 7 (Burgess reagent) and finally reduced to 8 (sodium cyanoborohydride). The
hydrogen atoms in 8 are in an undesired cis-relationship which contradicts the results obtained in
2002 by Bodwell/Li for the same reaction.

Vanderwal synthesis[edit]
In 2011, Vanderwal group reported a concise, longest linear sequence of 6 steps, total synthesis of
strychnine.[42] It featured a Zincke reaction followed by an anionic bicyclization reaction and a tandem Brook
rearrangement / conjugate addition.

External links[edit]

Strychnine Total Syntheses @ SynArchive.com