Strychnine total synthesis - AbsoluteAstronomy.com

Strychnine total synthesis in chemistry

Chemistry

Chemistry is the science of matter, especially its chemical reactions, but also its composition, structure and properties. Chemistry is concerned with atoms and their interactions with other atoms, and particularly with the properties of chemical bonds....

describes the total synthesis

Total synthesis

In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...

of the complex biomolecule

Biomolecule

A biomolecule is any molecule that is produced by a living organism, including large polymeric molecules such as proteins, polysaccharides, lipids, and nucleic acids as well as small molecules such as primary metabolites, secondary metabolites, and natural products...

strychnine

Strychnine

Strychnine is a highly toxic , colorless crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine causes muscular convulsions and eventually death through asphyxia or sheer exhaustion...

. The first reported method by the group of Robert Burns Woodward

Robert Burns Woodward

Robert Burns Woodward was an American organic chemist, considered by many to be the preeminent organic chemist of the twentieth century...

in 1954 is considered a classic in this research field.

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

Strychnos ignatia

Strychnos ignatia is a tree in the Loganiaceae family, native to the Philippines and parts of China. It is named for Saint Ignatius of Loyola, the founder of the Jesuit missionary order.-Fruit:...

by Pierre Joseph Pelletier

Pierre Joseph Pelletier

Pierre-Joseph Pelletier was a French chemist who did notable research on vegetable alkaloids, and was the co-discoverer of quinine and strychnine.- Further reading :...

and Joseph Bienaimé Caventou

Joseph Bienaimé Caventou

Joseph Bienaimé Caventou was a French chemist.He was a professor at the École de Pharmacie in Paris. He collaborated with Pierre-Joseph Pelletier in a Parisian laboratory located behind an apothecary. He was a pioneer in the use of mild solvents to isolate a number of active ingredients from...

in 1818. Major contributors to the entire effort were Sir Robert Robinson with over 250 publications and Hermann Leuchs

Hermann Leuchs

-Life:Leuchs studied chemistry at the University of Munich from 1898 till he changed to the University of Berlin He earned his Ph.D. with Hermann Emil Fischer in 1902 in Berlin. He steadily advanced in the hierarchy of the university, 1910 lecturer, assistant professor in 1914 and full professor in...

with another 125 papers in a time span of 40 years. Robinson was awarded the Nobel Prize in Chemistry

Nobel Prize in Chemistry

The Nobel Prize in Chemistry is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of chemistry. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outstanding contributions in chemistry, physics, literature,...

in 1947 for his work on alkaloids, strychnine included.

The process of chemical identification was completed with publications in 1946 by Robinson and later confirmed by Woodward in 1947. X-ray structures

X-ray crystallography

X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...

establishing the absolute configuration

Absolute configuration

An absolute configuration in stereochemistry is the spatial arrangement of the atoms of a chiral molecular entity and its stereochemical description e.g. R or S....

became available between 1947 and 1951 with publications from J. M. Bijvoet

Johannes Martin Bijvoet

Johannes Martin Bijvoet was a Dutch chemist and crystallographer at the van 't Hoff Laboratory at the University of Utrecht...

and J.H. Robertson
.

Woodward published a very brief account on the strychnine synthesis in 1954 (just 3 pages) and a lengthy one (42 pages) in 1963.

Many more methods exist and reported by the research groups of Magnus, Overman, Kuehne, Rawal, Bosch, Vollhardt, Mori,Shibasaki, Li, Fukuyama Vanderwal. Synthetic (+)-strychnine is also known. Racemic synthesises were published by Padwa in 2007 and in 2010 by Andrade and by Reissig.
In his 1963 publication Woodward quoted Sir Robert Robinson who said for its molecular size it is the most complex substance known.

The molecule

The C₂₁H₂₂N₂O₂ strychnine molecule contains 7 rings including an indoline

Indoline

Indoline is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing ring. The compound is based on the indole structure, but the 2-3 bond is saturated. by oxidation/dehydrogenation it can be...

system. It has a tertiary amine group, an amide

Amide

In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...

, an alkene

Alkene

In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...

and an ether

Ether

Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...

group. The naturally occurring compound is also chiral

Chirality (chemistry)

A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....

with 6 asymmetric carbon

Asymmetric carbon

An asymmetric carbon atom is a carbon atom that is attached to four different types of atom or four different groups of atoms. Knowing the number of asymmetric carbon atoms, one can calculate the maximum possible number of stereoisomers for any given molecule as follows:As an example, malic acid...

atoms including one quaternary one.

Ring II, V synthesis

The synthesis of ring II was accomplished with an Fischer indole synthesis

Fischer indole synthesis

The Fischer indole synthesis isa chemical reaction that produces the aromatic heterocycle indole from a phenylhydrazine and an aldehyde or ketone under acidic conditions. The reaction was discovered in 1883 by Hermann Emil Fischer. Today antimigraine drugs of the triptan class are often...

using phenylhydrazine

Phenylhydrazine

Phenylhydrazine is the chemical compound with the formula C6H5NHNH2. Organic chemists abbreviate the compound as PhNHNH2.- Chemical properties :...

1 and acetophenone

Acetophenone

Acetophenone is the organic compound with the formula C6H5CCH3. It is the simplest aromatic ketone. This colourless, viscous liquid is a precursor to useful resins and fragrances.-Production:Acetophenone can be obtained by a variety of methods...

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

Electrophilic substitution

Electrophilic substitution reactions are chemical reactions in which an electrophile displaces a group in a compound, typically but not always hydrogen. Electrophilic aromatic substitution is characteristic of aromatic compounds and is an important way of introducing functional groups onto benzene...

but will also become part of the strychnine skeleton. A Mannich reaction

Mannich reaction

The Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine. The final product is a β-amino-carbonyl compound also known as a Mannich base...

with formaldehyde

Formaldehyde

Formaldehyde is an organic compound with the formula CH2O. It is the simplest aldehyde, hence its systematic name methanal.Formaldehyde is a colorless gas with a characteristic pungent odor. It is an important precursor to many other chemical compounds, especially for polymers...

and dimethylamine

Dimethylamine

Dimethylamine is an organic compound with the formula 2NH. This secondary amine is a colorless, flammable liquified gas with an ammonia-like odor. Dimethylamine is generally encountered as a solution in water at concentrations up to around 40%...

) produced gramine

Gramine

Gramine is a naturally occurring indole alkaloid present in several plant species. Gramine may play a defensive role in these plants, since it is toxic to many organisms.-Occurrence:...

4. Alkylation

Alkylation

Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion or a carbene . Alkylating agents are widely used in chemistry because the alkyl group is probably the most common group encountered in...

with iodomethane

Iodomethane

Methyl iodide, also called iodomethane, and commonly abbreviated "MeI", is the chemical compound with the formula CH3I. It is a dense, colorless, volatile liquid. In terms of chemical structure, it is related to methane by replacement of one hydrogen atom by an atom of iodine. It is naturally...

gave an intermediate quaternary ammonium salt which reacted with sodium cyanide

Sodium cyanide

Sodium cyanide is an inorganic compound with the formula NaCN. This highly toxic colorless salt is used mainly in gold mining but has other niche applications...

in a nucleophilic substitution

Nucleophilic substitution

In organic and inorganic chemistry, nucleophilic substitution is a fundamental class of reactions in which an electron nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms called the leaving group; the positive or partially positive...

to cyanide

Cyanide

A cyanide is a chemical compound that contains the cyano group, -C≡N, which consists of a carbon atom triple-bonded to a nitrogen atom. Cyanides most commonly refer to salts of the anion CN−. Most cyanides are highly toxic....

5 and then in a reduction with lithium aluminium hydride

Lithium aluminium hydride

Lithium aluminium hydride, commonly abbreviated to LAH or known as LithAl, is an inorganic compound with the chemical formula LiAlH4. It was discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic synthesis, especially for the reduction of esters,...

to tryptamine

Tryptamine

Tryptamine is a monoamine alkaloid found in plants, fungi, and animals. It is based around the indole ring structure, and is chemically related to the amino acid tryptophan, from which its name is derived...

6. Amine-carbonyl condensation with ethyl glyoxylate give the imine

Imine

An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...

7. The reaction of this imine with TsCl

4-Toluenesulfonyl chloride

4-Toluenesulfonyl chloride is an organic compound with the formula CH3C6H4SO2Cl. This colourless, malodorous solid is a reagent widely used in organic synthesis...

in pyridine

Pyridine

Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...

to the ring-closed N-tosyl compound 8 was described by Woodward as a concerted nucleophilic enamine

Enamine

An enamine is an unsaturated compound derived by the reaction of an aldehyde or ketone with a secondary amine followed by loss of H2O.The word "enamine" is derived from the affix en-, used as the suffix of alkene, and the root amine. This can be compared with enol, which is a functional group...

attack and formally a Pictet–Spengler 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

Sodium borohydride

Sodium borohydride, also known as sodium tetrahydridoborate, is an inorganic compound with the formula NaBH4. This white solid, usually encountered as a powder, is a versatile reducing agent that finds wide application in chemistry, both in the laboratory and on a technical scale. Large amounts are...

to indoline

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

Indoline 9 was acetylated

Acetylation

Acetylation describes a reaction that introduces an acetyl functional group into a chemical compound...

to N-acetyl compound 10 (acetic anhydride

Acetic anhydride

Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...

, pyridine

Pyridine

Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...

) and then the veratryl group was then ring-opened with ozone

Ozone

Ozone , or trioxygen, is a triatomic molecule, consisting of three oxygen atoms. It is an allotrope of oxygen that is much less stable than the diatomic allotrope...

in aquaeous acetic acid

Acetic acid

Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...

to muconic ester

Muconic acid

Muconic acid is a dicarboxylic acid. There are three isomeric forms designated trans,trans-muconic acid, cis,trans-muconic acid, and cis,cis-muconic acid which differ by the geometry around the double bonds....

11 (made possible by the two electron-donating methoxide groups). This is an example of bioinspired synthesis already proposed by Woodward in 1948. Cleavage of the acetyl group and ester hydrolysis with HCl

HCL

HCL or HCl can stand for:* Hairy cell leukemia, an uncommon and slowly progressing B cell leukemia* Hardware compatibility list...

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

Hydrogen iodide

Hydrogen iodide is a diatomic molecule. Aqueous solutions of HI are known as iohydroic acid or hydroiodic acid, a strong acid. Gas and aqueous solution are interconvertible...

and red phosphorus removed the tosyl group and hydrolysed both remaining ester groups to form diacid 13. Acetylation and esterfication (diazomethane

Diazomethane

Diazomethane is the chemical compound CH2N2. It is the simplest of diazo compounds. In the pure form at room temperature, it is a extremely sensitive explosive yellow gas, thus it is almost universally used as a solution in diethyl ether...

) produced acetyl diester 14 which was then subjected to a Dieckman condensation with sodium methoxide

Sodium methoxide

Sodium methoxide is a chemical compound, with formula CH3ONa. This colourless solid, which is formed by the deprotonation of methanol, is a widely used reagent in industry and the laboratory...

in methanol to enol

Enol

Enols are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Alkenes with a hydroxyl group on both sides of the double bond are called enediols. Deprotonated anions of enols are called enolates...

15.

Ring VII synthesis

In order to remove the C15 alcohol

Alcohol

In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....

group, Enol

Enol

15 was converted to tosylate 16 (TsCl, pyridine

Pyridine

Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...

) and then to mercaptoester 17 (sodium benzylmercaptide) which was then reduced to unsaturated ester 18 by Raney nickel

Raney nickel

Raney nickel is a solid catalyst composed of fine grains of a nickel-aluminium alloy, used in many industrial processes. It was developed in 1926 by American]] engineer Murray Raney as an alternative catalyst for the hydrogenation of vegetable oils in industrial processes...

and hydrogen

Hydrogen

Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...

. Further reduction with hydrogen / palladium on carbon

Palladium on carbon

Palladium on carbon, often referred to as Pd/C, is a form of palladium used for catalysis. It is usually used for catalytic hydrogenations in organic chemistry...

afforded the saturated ester 19. Alkaline ester hydrolysis to carboxylic acid

Carboxylic acid

Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...

20 was accompanied by epimerization at C14.

This particular compound was already known from strychnine degration studies. Until now all intermediates were racemic

Racemic

In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...

but chirality was introduced at this particular stage via chiral resolution

Chiral resolution

Chiral resolution in stereochemistry is a process for the separation of racemic compounds into their enantiomers. It is an important tool in the production of optically active drugs...

using quinidine

Quinidine

Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...

.

The C20 carbon atom was then introduced by acetic anhydride

Acetic anhydride

to form enol acetate 21 and the free aminoketone 22 was obtained by hydrolysis with hydrochloric acid

Hydrochloric acid

Hydrochloric acid is a solution of hydrogen chloride in water, that is a highly corrosive, strong mineral acid with many industrial uses. It is found naturally in gastric acid....

. Ring VII in intermediate 23 was closed by selenium dioxide

Selenium dioxide

Selenium dioxide is the chemical compound with the formula SeO2. This colorless solid is one of the most frequently encountered compounds of selenium.-Properties:...

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

Carbon dioxide

Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...

and again acylation:

Ring VI synthesis

To diketone

Diketone

A diketone is a molecule containing two ketone groups. The simpliest diketone is diacetyl, also known as 2,3-butanedione. Diacetyl, acetylacetone, and hexane-2,5-dione are examples of 1,2-, 1,3-, and 1,4-diketones, respectively...

23 was added sodium acetylide (bringing in carbon atoms 22 and 23) to give alkyne

Alkyne

Alkynes are hydrocarbons that have a triple bond between two carbon atoms, with the formula CnH2n-2. Alkynes are traditionally known as acetylenes, although the name acetylene also refers specifically to C2H2, known formally as ethyne using IUPAC nomenclature...

24. This compound was reduced to the allyl alcohol

Allyl alcohol

Allyl alcohol is an organic compound with the structural formula CH2=CHCH2OH. Like many alcohols,it is a water soluble, colourless liquid, but it is more toxic than typical small alcohols. Allyl alcohol is used as a raw material for the production of glycerol, but is used as a precursor to many...

25 using the Lindlar catalyst

Lindlar catalyst

A Lindlar catalyst is a heterogeneous catalyst that consists of palladium deposited on calcium carbonate and treated with various forms of lead. The lead additive serves to deactivate the palladium sites. A variety of "catalyst poisons" have been used including lead acetate and lead oxide. The...

and lithium aluminium hydride

Lithium aluminium hydride

removed the remaining ketone

Ketone

In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...

group in 26. An allylic rearrangement

Allylic rearrangement

An allylic rearrangement or allylic shift is an organic reaction in which the double bond in an allyl chemical compound shifts to the next carbon atom. It is encountered in nucleophilic substitution....

to alcohol 27 (isostrychnine) was brought about by hydrogen bromide

Hydrogen bromide

Hydrogen bromide is the diatomic molecule HBr. HBr is a gas at standard conditions. Hydrobromic acid forms upon dissolving HBr in water. Conversely, HBr can be liberated from hydrobromic acid solutions with the addition of a dehydration agent, but not by distillation. Hydrogen bromide and...

in acetic acid followed by hydrolysis with sulfuric acid

Sulfuric acid

Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...

. In the final step to (-)-strychnine 28 treatment of 27 with ethanolic potassium hydroxide

Potassium hydroxide

Potassium hydroxide is an inorganic compound with the formula KOH, commonly called caustic potash.Along with sodium hydroxide , this colorless solid is a prototypical strong base. It has many industrial and niche applications. Most applications exploit its reactivity toward acids and its corrosive...

caused rearrangement of the C12-13 double bond and ring closure in a conjugate addition by the hydroxyl anion.

Magnus synthesis

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

Wieland-Gumlich aldehyde

The Wieland-Gumlich aldehyde is an indoline derived from strychnine. This compound is of some commercial interest as a chemical intermediate. It was first synthesized in 1932 by Wieland and Gumlich in 4 steps from strychnine...

. In the final leg strychnine itself was synthesised from the relay compound.

Overman synthesis

The Overman

Larry E. Overman

Larry E. Overman is Distinguished Professor of Chemistry at the University of California, Irvine. He was born in Chicago in 1943. Overman obtained a B.A. degree from Earlham College in 1965. and he completed his Ph.D. in chemistry from the University of Wisconsin–Madison in 1969, under Howard...

synthesis (1993) took a chiral

Chirality (chemistry)

cyclopentene

Cyclopentene

Cyclopentene is a chemical compound with the formula 58. It is a colorless liquid with a petrol-like odor. It is one of the cycloalkenes.Cyclopentene is produced industrially in large amounts...

compound as starting material obtained by enzymatic hydrolysis

Hydrolysis

Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...

of cis-1,4-diacetoxycyclopent-2-ene. This starting material was converted in several steps to trialkylstannane

Organotin

Organotin compounds or stannanes are chemical compounds based on tin with hydrocarbon substituents. Organotin chemistry is part of the wider field of organometallic chemistry. The first organotin compound was diethyltin diiodide, discovered by Edward Frankland in 1849...

1 which was then coupled with an aryl iodide 2 in a Stille reaction

Stille reaction

The Stille reaction is a chemical reaction coupling an organotin compound with an sp2-hybridized organic halide catalyzed by palladium. The reaction is widely used in organic synthesis....

in presence of carbon monoxide

Carbon monoxide

Carbon monoxide , also called carbonous oxide, is a colorless, odorless, and tasteless gas that is slightly lighter than air. It is highly toxic to humans and animals in higher quantities, although it is also produced in normal animal metabolism in low quantities, and is thought to have some normal...

(tris(dibenzylideneacetone)dipalladium(0)

Tris(dibenzylideneacetone)dipalladium(0)

Trisdipalladium or Pd23 is an organometallic complex based on palladium and dibenzylideneacetone used in organic chemistry. It was discovered in 1970.-Preparation and structure:...

, triphenylarsine

Triphenylarsine

Triphenylarsine is the chemical compound with the formula As3. This organoarsenic compound, often abbreviated AsPh3, is a colorless crystalline solid that is used as a ligand and a reagent in coordination chemistry and organic synthesis...

). The internal double in 3 was converted to an epoxide

Epoxide

An epoxide is a cyclic ether with three ring atoms. This ring approximately defines an equilateral triangle, which makes it highly strained. The strained ring makes epoxides more reactive than other ethers. Simple epoxides are named from the parent compound ethylene oxide or oxirane, such as in...

using tert-Butyl hydroperoxide

Tert-Butyl hydroperoxide

tert-Butyl hydroperoxide is an organic peroxide widely used in a variety of oxidation processes, for example Sharpless epoxidation...

, the carbonyl

Carbonyl

In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....

group was then converted to an alkyne

Alkyne

in a Wittig reaction

Wittig reaction

The Wittig reaction is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide to give an alkene and triphenylphosphine oxide....

using Ph₃P=CH₂ and the TIPS

Tips

Tips may refer to:* Tip , extra payment left by guests* Tips Industries, an Indian film production company* Gambling suggestions made by a TipsterTIPS as an acronym may refer to:* Operation TIPS, Terrorism Information and Prevention System...

group was hydrolyzed (TBAF) and replaced by a trifluoroacetamide group (NH₂COCF₃, NaH

Nah

Nah, nah, or NaH may refer to:*Nah, Iran, a city in South Khorasan Province, Iran* Sodium hydride, whose chemical formula is NaH* The language code nah, which stands for Nahuatl...

) 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

Cope reaction

The Cope reaction or Cope elimination, developed by Arthur C. Cope, is an elimination reaction of an amine oxide to form an alkene and a hydroxylamine. The reaction mechanism involves an intramolcular 5-membered cyclic transition state, leading to a syn elimination product...

Mannich reaction

initiated by a amine-carbonyl condensation using formaldehyde

Formaldehyde

and forming 6 in a quantitative yield:

In the final sequence strychnine was obtained through the Wieland-Gumlich aldehyde

Wieland-Gumlich aldehyde

(10):

Intermediate 6 was acylated using methyl cyanoformate

Methyl cyanoformate

Methyl cyanoformate is the organic compound with the formula CH3OCCN. This colorless liquid is used as a reagent in organic synthesis as a source of the methoxycarbonyl group.It was also the active ingredient in the pesticide product Zyklon A....

and two protective groups (tert-butyl and ) were removed using HCl

HCL

HCL or HCl can stand for:* Hairy cell leukemia, an uncommon and slowly progressing B cell leukemia* Hardware compatibility list...

/ MeOH in 7. The C8C13 double bond was reduced with zinc

Zinc

Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...

(MeOH/H⁺) to saturated ester 8 (mixture). Epimerization at C13 with sodium methoxide

Sodium methoxide

Sodium methoxide is a chemical compound, with formula CH3ONa. This colourless solid, which is formed by the deprotonation of methanol, is a widely used reagent in industry and the laboratory...

in MeOH produced beta-ester 9 which was reduced with diisobutylaluminium hydride
to Wieland-Gumlich aldehyde 10. Conversion of this compound with malonic acid

Malonic acid

Malonic acid is a dicarboxylic acid with structure CH22. The ionised form of malonic acid, as well as its esters and salts, are known as malonates. For example, diethyl malonate is malonic acid's ethyl ester...

to (-)-strychnine 11 was already known as a procedure.

Kuehne synthesis

The 1993 Keuhne synthesis concerns racemic

Racemic

strychnine. Starting compounds tryptamine

Tryptamine

1 and 4,4-dimethoxy acrolein

Acrolein

Acrolein is the simplest unsaturated aldehyde. It is produced widely but is most often immediately reacted with other products due to its instability and toxicity...

2 were reacted together with boron trifluoride

Boron trifluoride

Boron trifluoride is the chemical compound with the formula BF3. This pungent colourless toxic gas forms white fumes in moist air. It is a useful Lewis acid and a versatile building block for other boron compounds.-Structure and bonding:...

to acetal

Acetal

An acetal is a molecule with two single-bonded oxygen atoms attached to the same carbon atom.Traditional usages distinguish ketals from acetals...

3 as a single diastereomer

Diastereomer

Diastereomers are stereoisomers that are not enantiomers.Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of each other.When two diastereoisomers differ from each other at...

in a amine-carbonyl condensation / sigmatropic rearrangement sequence.

Hydrolysis

with perchloric acid

Perchloric acid

Perchloric acid is the inorganic compound with the formula HClO4. Usually encountered as an aqueous solution, this colourless compound is a strong acid comparable in strength to sulfuric and nitric acids. It is a powerful oxidizer, but its aqueous solutions up to appr. 70% are remarkably inert,...

afforded aldehyde

Aldehyde

An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....

4. A Johnson-Corey-Chaykovsky reaction

Johnson-Corey-Chaykovsky reaction

The Johnson–Corey–Chaykovsky reaction is a chemical reaction used in organic chemistry for the synthesis of epoxides, aziridines, and cyclopropanes. It was discovered in 1961 by A. William Johnson and developed significantly by E.J. Corey and Michael Chaykovsky...

(trimethylsulfonium iodide / n-butyllithium

N-Butyllithium

n-Butyllithium is an organolithium reagent. It is widely used as a polymerization initiator in the production of elastomers such as polybutadiene or styrene-butadiene-styrene...

) converted the aldehyde into an epoxide

Epoxide

which reacted in situ with the tertiary amine to ammonium salt 5 (contaminated with other cyclization products). Reduction (palladium on carbon

Palladium on carbon

Palladium on carbon, often referred to as Pd/C, is a form of palladium used for catalysis. It is usually used for catalytic hydrogenations in organic chemistry...

/hydrogen

Hydrogen

) removed the benzyl

Benzyl

In organic chemistry, benzyl is the term used to describe the substituent or molecular fragment possessing the structure C6H5CH2-. Benzyl features a benzene ring attached to a CH2 group.-Nomenclature:...

group to alcohol

Alcohol

6, more reduction (sodium cyanoborohydride

Sodium cyanoborohydride

Sodium cyanoborohydride is the inorganic compound with the formula NaBH3. This colourless salt is widely used in organic synthesis for the reduction of imines.-Preparation and use:...

) and acylation

Acylation

In chemistry, acylation is the process of adding an acyl group to a compound. The compound providing the acyl group is called the acylating agent....

(acetic anhydride

Acetic anhydride

/ pyridine

Pyridine

Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...

) produced 7 as a mixture of epimers (at C17). Ring closure of ring III to 8 was then accomplished with an aldol reaction

Aldol reaction

The aldol reaction is a powerful means of forming carbon–carbon bonds in organic chemistry.Discovered independently by Charles-Adolphe Wurtz and Alexander Porfyrevich Borodin in 1872, the reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound...

using lithium bis(trimethylsilyl)amide

Lithium bis(trimethylsilyl)amide

Lithium bisamide is the organosilicon compound with the formula [3Si]2NLi. This colourless solid is a strong non-nucleophilic base used for deprotonation reactions and as a ligand...

(using only the epimer with correct configuration). Even more reduction (sodium borohydride

Sodium borohydride

) and acylation resulted in epimeric di-acetate 9.

A DBU mediated elimination reaction

Elimination reaction

An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism...

formed olefinic alcohol 10 and subsequent Swern oxidation

Swern oxidation

The Swern oxidation, named after Daniel Swern, is a chemical reaction whereby a primary or secondary alcohol is oxidized to an aldehyde or ketone using oxalyl chloride, dimethyl sulfoxide and an organic base, such as triethylamine...

have an unstable amino ketone

Ketone

11. In the final steps a Horner–Wadsworth–Emmons reaction (methyl 2-(diethy1phosphono)acetate) give acrylate

Acrylate

The acrylate ion is the ion of acrylic acid.Acrylates are the salts and esters of acrylic acid. They are also known as propenoates ....

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

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

Tryptophan

Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...

Rawal synthesis

In the Rawal synthesis (1994, racemic) amine

Amine

Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...

1 and enone

Enone

An enone is an unsaturated chemical compound or functional group consisting of a conjugated system of an alkene and a ketone. The simplest enone is methyl vinyl ketone or CH2=CHCOCH3....

2 were combined in a amine-carbonyl condensation followed by methyl chloroformate

Chloroformate

Chloroformates are a class of chemical compounds which are esters of chloroformic acid. They are widely used as reagents in organic chemistry. For example, benzyl chloroformate is used to introduce the CBZ protecting group and fluorenylmethyloxycarbonylchloride is used to introduce the FMOC...

quench to triene 3 which was then reacted in a Diels-Alder reaction

Diels-Alder reaction

The Diels–Alder reaction is an organic chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. The reaction can proceed even if some of the atoms in the newly formed ring are not carbon...

(benzene 185°C) to hexene 4. The three ester groups were hydrolyzed using iodotrimethylsilane forming pentacyclic lactam

Lactam

A lactam is a cyclic amide. Prefixes indicate how many carbon atoms are present in the ring: β-lactam , γ-lactam , δ-lactam...

5 after a methanol quench in a combination of 7 reaction steps (one of them a Dieckmann condensation

Dieckmann condensation

The Dieckmann condensation is the intramolecular chemical reaction of diesters with base to give β-ketoesters. It is named after the German chemist Walter Dieckmann . The equivalent intermolecular reaction is the Claisen condensation....

). The C₄ segment 6 was added in an amine alkylation

Amine alkylation

Amine alkylation is a type of organic reaction between an alkyl halide and ammonia or an amine. The reaction is called nucleophilic aliphatic substitution , and the reaction product is a higher substituted amine...

and Heck reaction

Heck reaction

The Heck reaction is the chemical reaction of an unsaturated halide with an alkene and a base and palladium catalyst to form a substituted alkene. Together with the other palladium-catalyzed cross-coupling reactions, this reaction is of great importance, as it allows one to do substitution...

of 7 formed isostrychnine 8 after TBS deprotection.

Bosch synthesis

In the Bosch synthesis of (1999, chiral) the olefin group in dione 1 was converted to an aldehyde

Aldehyde

An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....

by ozonolysis

Ozonolysis

Ozonolysis is the cleavage of an alkene or alkyne with ozone to form organic compounds in which the multiple carbon–carbon bond has been replaced by a double bond to oxygen...

and chiral amine 2 was formed in a double reductive amination

Reductive amination

Reductive amination is a form of amination that involves the conversion of a carbonyl group to an amine via an intermediate imine...

with (S)-1-phenylethylamine. The phenylethyl substituent

Substituent

In organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon...

was removed using ClCO₂CHClCH₃ and the enone

Enone

An enone is an unsaturated chemical compound or functional group consisting of a conjugated system of an alkene and a ketone. The simplest enone is methyl vinyl ketone or CH2=CHCOCH3....

group was introduced in a Grieco elimination

Grieco elimination

The Grieco elimination is an organic reaction describing the elimination reaction of an aliphatic primary alcohol through a selenide to a terminal alkene ....

using TMSI, HMDS

Bis(trimethylsilyl)amine

Bisamine is an organosilicon compound with the molecular formula [3Si]2NH. The molecule is a derivative of ammonia with trimethylsilyl groups in place of two hydrogen atoms...

then PhSeCl then ozone

Ozone

Ozone , or trioxygen, is a triatomic molecule, consisting of three oxygen atoms. It is an allotrope of oxygen that is much less stable than the diatomic allotrope...

and then diisopropylamine

Diisopropylamine

Diisopropylamine is a secondary amine with the chemical formula 2HC-NH-CH2. It is best known as its lithium salt, lithium diisopropylamide, known as "LDA"...

forming carbamate

Carbamate

Carbamates are organic compounds derived from carbamic acid . A carbamate group, carbamate ester, and carbamic acids are functional groups that are inter-related structurally and often are interconverted chemically. Carbamate esters are also called urethanes.-Synthesis:Carbamic acids are derived...

3. The amino group was deprotected by refluxing in methanol and then alkylated

Amine alkylation

using (Z)-BrCH₂CICH=CH₂OTBDMS, to tertiary amine 4. A reductive Heck reaction

Heck reaction

took place next followed by methoxycarbonylation (LiHMDS, NCCO₂Me) to tricycle 5. Reaction with zinc

Zinc

dust in 10% sulfuric acid

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

Wieland-Gumlich aldehyde

7 reaction with NaH

Sodium hydride

Sodium hydride is the chemical compound with the empirical formula NaH. It is primarily used as a strong base in organic synthesis. NaH is representative of the saline hydrides, meaning it is a salt-like hydride, composed of Na+ and H− ions, in contrast to the more molecular hydrides such as...

in MeOH afforded the correct epimer was followed by DIBAH reduction of the methyl ester.

Vollhardt synthesis

The key reaction in the Vollhardt synthesis (2000, racemic) was an alkyne trimerisation

Alkyne trimerisation

An alkyne trimerisation reaction is a 2+2+2 cyclization reaction in which three alkyne molecules react to form an aromatic compound. The reaction is 'pseudo' pericyclic since it has not been observed to occur without the assistance of metal catalysis; and the metal catalyst assembles the ring...

of tryptamine

Tryptamine

derivative 1 with acetylene

Acetylene

Acetylene is the chemical compound with the formula C2H2. It is a hydrocarbon and the simplest alkyne. This colorless gas is widely used as a fuel and a chemical building block. It is unstable in pure form and thus is usually handled as a solution.As an alkyne, acetylene is unsaturated because...

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

Amine alkylation

with (Z)-1-bromo-4-[(tert-butyldimethylsilyl)oxy]-2-iodobut-2-ene (see Rawal synthesis) and lithium carbonate

Lithium carbonate

Lithium carbonate is a chemical compound of lithium, carbon, and oxygen with the formula Li2CO3. This colorless salt is widely used in the processing of metal oxides and has received attention for its use in psychiatry. It is found in nature as the rare mineral zabuyelite.-Properties:Like almost...

, and isomerization of the diene

Diene

In organic chemistry a diene or diolefin is a hydrocarbon that contains two carbon double bonds.Conjugated dienes are functional groups, with a general formula of CnH2n-2. Dienes and alkynes are functional isomers...

system (NaOiPr, iPrOH) formed enone 4. A Heck reaction

Heck reaction

as in the Rawal synthesis (palladium acetate / triphenylphosphine

Triphenylphosphine

Triphenylphosphine is a common organophosphorus compound with the formula P3 - often abbreviated to PPh3 or Ph3P. It is widely used in the synthesis of organic and organometallic compounds. PPh3 exists as relatively air stable, colorless crystals at room temperature...

), accompanied by aromatization formed pyridone 5 and lithium aluminium hydride

Lithium aluminium hydride

reduction and TBS group deprotection formed isostrychnine 6.

Mori synthesis

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 1 reacted with allyl carbonate 2 in an allylic asymmetric substitution using Pd₂(dba)₃

Tris(dibenzylideneacetone)dipalladium(0)

Trisdipalladium or Pd23 is an organometallic complex based on palladium and dibenzylideneacetone used in organic chemistry. It was discovered in 1970.-Preparation and structure:...

and asymmetric ligand (S-BINAPO) to chiral secondary amine 3. Desilylation of the TBDMS group next took place by HCl

HCL

HCL or HCl can stand for:* Hairy cell leukemia, an uncommon and slowly progressing B cell leukemia* Hardware compatibility list...

to the hydroxide

Alcohol

and then to the nitrile

Nitrile

A nitrile is any organic compound that has a -C≡N functional group. The prefix cyano- is used interchangeably with the term nitrile in industrial literature. Nitriles are found in many useful compounds, one example being super glue .Inorganic compounds containing the -C≡N group are not called...

4 (NaCN) through the bromide (PBr₃

Phosphorus tribromide

Phosphorus tribromide is a colourless liquid with the formula PBr3. It fumes in air due to hydrolysis and has a penetrating odour. It is widely used in the laboratory for the conversion of alcohols to alkyl bromides.-Preparation:...

). Heck reaction

Heck reaction

(Pd(OAc)₂ / Me₂PPh

Dimethylphenylphosphine

Dimethylphenylphosphine is a organophosphorus compound with a formula P2. The phosphorus is connected to a phenyl group and two methyl groups. This colorless air sensitive liquid is commonly used as a ligand in transition metal complexes...

) and debromination (Ag₂CO₃

Silver carbonate

Silver carbonate is the chemical compound with the formula Ag2CO3. Silver carbonate is yellow but typical samples are grayish due to the presence of elemental silver. It is poorly soluble in water, like most transition metal carbonates. Silver carbonate is used as a reagent in organic synthesis...

) afforded tricycle 5. LiALH₄

Lithium aluminium hydride

Nitrile reduction

In nitrile reduction a nitrile is reduced to either an amine or an aldehyde with a suitable chemical reagent .Reagents for the conversion to amines are lithium aluminium hydride, Raney nickel / hydrogen / or diborane This organic reaction is one of several nitrogen-hydrogen bond forming...

to the amine

Amine

and its Boc₂O

Di-tert-butyl dicarbonate

Di-tert-butyl dicarbonate is a reagent widely used in organic synthesis. This carbonate ester reacts with amines to give N-tert-butoxycarbonyl or so-called t-BOC derivatives. These derivatives do not behave as amines, which allows certain subsequent transformations to occur that would have...

protection to boc amine 6 was then followed by a second allylic oxidation (Pd(OAc)₂ / AcOH

Acetic acid

/ benzoquinone / MnO₂

Manganese oxide

Manganese oxide is a generic term used to describe a variety of manganese oxides and hydroxides. It may refer to:* Manganese oxide, MnO* Manganese oxide, Mn3O4* Manganese oxide, Mn2O3* Manganese dioxide, , MnO2...

) to tetracycle 7. Hydroboration-oxidation (9-BBN

9-BBN

9-Borabicyclo[3.3.1]nonane or 9-BBN is an organoborane compound. This colourless solid is used in organic chemistry as a hydroboration reagent. The compound exists as a hydride-bridged dimer, which easily cleaves in the presence of reducible substrates...

/ H₂O₂

Hydrogen peroxide

Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...

) gave alcohol

Alcohol

8 and subsequent Swern oxidation

Swern oxidation

ketone 9. Reaction with LDA

Lithium diisopropylamide

Lithium diisopropylamide is the chemical compound with the formula [2CH]2NLi. Generally abbreviated LDA, it is a strong base used in organic chemistry for the deprotonation of weakly acidic compounds. The reagent has been widely accepted because it is soluble in non-polar organic solvents and it...

/ PhNTf₂ gave enol triflate 10 and the triflate group was removed in alkene

Alkene

In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...

11 by reaction with Pd(OAc)₂ and PPh₃

Triphenylphosphine

Detosylation of 11 (sodium naphthalenide

Sodium naphthalenide

Sodium naphthalenide, also known as sodium naphthalide, is a soluble one-electron reductant employed in organic, organometallic, and inorganic chemistry. It is prepared by stirring sodium metal with naphthalene in a polar solvent such as tetrahydrofuran or dimethoxyethane, resulting in the...

) and amidation with acid chloride 3-bromoacryloyl chloride gave amide 12 and another Heck reaction

Heck reaction

gave pentacycle 13. double bond isomerization (sodium

Sodium

Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...

/ iPrOH

Isopropyl alcohol

Isopropyl alcohol is a common name for a chemical compound with the molecular formula C3H8O. It is a colorless, flammable chemical compound with a strong odor...

), Boc group deprotection (triflic acid) and amine alkylation

Amine alkylation

with (Z)-BrCH₂CICH=CH₂OTBDMS (see Rawal) gave compound 14 (identical to one of the Vollhardt intermediates). A final heck reaction

Heck reaction

(15) and TBDMS deprotection formed (-)-isostrychnine 16.

Shibasaki synthesis

The Shibasaki synthesis ((-) chiral, 2002) was a second published method in strychnine total synthesis using an asymmetric reaction step. Cyclohexenone

Cyclohexenone

Cyclohexenone is an organic compound which is a versatile intermediate used in the synthesis of a variety of chemical products such as pharmaceuticals and fragrances...

1 was reacted with dimethyl malonate

Dimethyl malonate

Dimethyl malonate is a diester derivative of malonic acid. It is a common reagent for organic synthesis. It is used in the malonic ester synthesis....

2 in an asymmetric Michael reaction using AlLibis(binaphthoxide) to form chiral diester 3. It's ketone

Ketone

group was protected as an acetal

Acetal

An acetal is a molecule with two single-bonded oxygen atoms attached to the same carbon atom.Traditional usages distinguish ketals from acetals...

(2-ethyl-2-methyl-1,3-dioxolane, TsOH) and a carboxyl group was removed (LiCl, DMSO

Dimethyl sulfoxide

Dimethyl sulfoxide is an organosulfur compound with the formula 2SO. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water...

140 °C) in monoester 4. A C2 fragment was added as Weinreb amide 5 to form PMB ether 6 using LDA

Lithium diisopropylamide

. The ketone was then reduced to the alcohol (NaBH₃CN

Sodium cyanoborohydride

Sodium cyanoborohydride is the inorganic compound with the formula NaBH3. This colourless salt is widely used in organic synthesis for the reduction of imines.-Preparation and use:...

, TiCl₄

Titanium tetrachloride

Titanium tetrachloride is the inorganic compound with the formula TiCl4. It is an important intermediate in the production of titanium metal and the pigment titanium dioxide. TiCl4 is an unusual example of a metal halide that is highly volatile...

) and then water was eliminated

Elimination reaction

An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism...

(DCC, CuCl

Copper(I) chloride

Copper chloride, commonly called cuprous chloride, is the lower chloride of copper, with the formula CuCl. The substance is a white solid sparingly soluble in water, but very soluble in concentrated hydrochloric acid...

) to form alkene

Alkene

In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...

7. After ester

Ester

Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...

reduction (DIBAL) to the alcohol and its TIPS protection (TIPSOTf, triethylamine

Triethylamine

Triethylamine is the chemical compound with the formula N3, commonly abbreviated Et3N. It is also abbreviated TEA, yet this abbreviation must be used carefully to avoid confusion with triethanolamine, for which TEA is also a common abbreviation....

), the acetal group was removed (catalytic CSA

Camphorsulfonic acid

Camphorsulfonic acid, sometimes abbreviated CSA or 10-CSA is a organosulfur compound. Like typical sulfonic acids, it is a relatively strong acid that exists as a colourless solid that is soluble in organic solvents....

) in ketone 8. Enone

Enone

An enone is an unsaturated chemical compound or functional group consisting of a conjugated system of an alkene and a ketone. The simplest enone is methyl vinyl ketone or CH2=CHCOCH3....

9 was then formed by Saegusa oxidation. The conversion to alcohol 10 was accomplished via a Mukaiyama aldol addition

Mukaiyama aldol addition

The Mukaiyama aldol addition is an organic reaction and a type of aldol reaction between a silyl enol ether and an aldehyde catalyzed by a Lewis acid. This choice of reactants allows for a crossed aldol reaction between an aldehyde and a ketone or a different aldehyde without self-condensation of...

using formaldehyde

Formaldehyde

, iodonation to 11 (iodine

Iodine

Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....

, DMAP) was followed by a Stille coupling (Pd₂dba₃

Tris(dibenzylideneacetone)dipalladium(0)

Trisdipalladium or Pd23 is an organometallic complex based on palladium and dibenzylideneacetone used in organic chemistry. It was discovered in 1970.-Preparation and structure:...

, Ph₃As

Triphenylarsine

, CuI

Cui

-People:* Cui, Chinese surname.* César Cui , a Russian composer* Jorge "Cui" Cuello, British historian Oxford University, 1995 Pulitzer Prize winner-Other uses:* Cui , a Peruvian term for the guinea pig, when used as food...

) incorporating nitrobenzene

Nitrobenzene

Nitrobenzene is an organic compound with the chemical formula C6H5NO2. It is a water-insoluble pale yellow oil with an almond-like odor. It freezes to give greenish-yellow crystals. It is produced on a large scale as a precursor to aniline. Although occasionally used as a flavoring or perfume...

unit 12. Alcohol 13 was formed after SEM

Silyl ether

Silyl ethers are a group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl group. Silyl ethers are usually used as protecting groups for alcohols in organic synthesis...

protection (SEMCl,i-Pr2NEt) and TIPS removal (HF

Hydrofluoric acid

Hydrofluoric acid is a solution of hydrogen fluoride in water. It is a valued source of fluorine and is the precursor to numerous pharmaceuticals such as fluoxetine and diverse materials such as PTFE ....

In the second part of the sequence alcohol 13 was converted to a triflate (Triflic anhydride

Triflic anhydride

Triflic anhydride is the chemical compound with the formula 2O. This compound is a particularly strong electrophile, useful for introducing the triflyl group, CF3SO2. Triflic anhydride is the acid anhydride of the strong acid triflic acid, CF3SO2OH....

, N,N-Diisopropylethylamine), then 2,2-bis(ethylthio)ethylamine 14 was added immediately followed by zinc

Zinc

powder, setting of a tandem reaction with nitro group reduction to the amine, 1,4-addition of the thio-amine group and amine-keto condensation to indole 16. Reaction with DMTSF gave thionium attack at C7 forming 17, the imine

Imine

group was then reduced (NaBH₃CN

Sodium cyanoborohydride

Sodium cyanoborohydride is the inorganic compound with the formula NaBH3. This colourless salt is widely used in organic synthesis for the reduction of imines.-Preparation and use:...

, TiCl₄

Titanium tetrachloride

), the new amino group acylated

Acylation

In chemistry, acylation is the process of adding an acyl group to a compound. The compound providing the acyl group is called the acylating agent....

(acetic anhydride

Acetic anhydride

, pyridine

Pyridine

Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...

), both alcohol protecting groups removed (NaOMe / meOH) and the allyl alcohol group protected again (TIPS). This allowed removal of the ethylthio group (NiCl₂

Nickel(II) chloride

Nickel chloride , is the chemical compound NiCl2. The anhydrous salt is yellow, but the more familiar hydrate NiCl2·6H2O is green. It is very rarely found in nature as mineral nickelbischofite. A dihydrate is also known. In general nickel chloride, in various forms, is the most important source of...

, NaBH₄

Sodium borohydride

, EtOH/MeOH) to 18. The alcohol was oxidized to the aldehyde using a Parikh-Doering oxidation

Parikh-Doering oxidation

The Parikh-Doering oxidation is an oxidation reaction that transforms primary and secondary alcohols into aldehydes and ketones, respectively. The procedure uses DMSO as the oxidant, activated by sulfur trioxide-pyridine complex in the presence of triethylamine base:The procedure can be run at...

and TIPS group removal gave hemiacetal 19 called (+)-diaboline which is acylated Wieland-Gumlich aldehyde

Wieland-Gumlich aldehyde

Li synthesis

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

Cyclophane

A cyclophane is a hydrocarbon consisting of an aromatic unit and an aliphatic chain that forms a bridge between two non-adjacent positions of the aromatic ring. More complex derivatives with multiple aromatic units and bridges forming cagelike structures are also known...

1 by heating in N,N-diethylaniline (dinitrogen is expulsed) followed by reduction of double bond in 2 to 3 by sodium borohydride

Sodium borohydride

/ triflic acid and removal of the carbamate

Carbamate

protecting group

Protecting group

A protecting group or protective group is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction...

(PDC / celite) to 4.

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

Fukuyama synthesis

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

Acyloin

Acyloins are a class of organic compounds in organic chemistry sharing a common functional group consisting of a hydroxyl group placed on the α-position of a carbonyl group.- Nomenclature :Common types of ketols include:...

2 was formed by Rubottom oxidation

Rubottom oxidation

The Rubottom oxidation is the chemical reaction of enolsilanes with m-chloroperoxybenzoic acid to give silyl-protected α-hydroxy ketones.-Reaction mechanism:...

and hydrolysis. Oxidative cleavage by lead acetate

Lead acetate

Lead acetate can refer to:* Lead acetate , Pb4* Lead acetate , Pb2...

formed aldehyde 3, removal of the nosyl group (thiophenol

Thiophenol

Thiophenol is an organosulfur compound with the formula C6H6S, and sometimes abbreviated as PhSH. This foul-smelling colourless liquid is the simplest aromatic thiol. The chemical structures of thiophenols are analogous to phenols except the oxygen atom in the hydroxyl group bonded to the...

/ 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

Wieland-Gumlich aldehyde

by known chemistry.

Reissig synthesis

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

Cascade reaction

A cascade reaction or tandem reaction or domino reaction is a consecutive series of intramolecular organic reactions which often proceed via highly reactive intermediates. It allows the organic synthesis of complex multinuclear molecules from a single acyclic precursor. The substrate contains many...

using samarium diiodide and HMPA. Raney nickel

Raney nickel

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

Chloroformate

, DMAP and TEA

Tea

Tea is an aromatic beverage prepared by adding cured leaves of the Camellia sinensis plant to hot water. The term also refers to the plant itself. After water, tea is the most widely consumed beverage in the world...

then MsCl, DMAP and TEA

Triethanolamine

Triethanolamine, often abbreviated as TEA, is an organic chemical compound which is both a tertiary amine and a triol. A triol is a molecule with three alcohol groups. Like other amines, triethanolamine is a strong base due to the lone pair of electrons on the nitrogen atom. Triethanolamine can...

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

Imine

5 then converted to carbamate

Carbamate

6, then dehydrated to diene 7 (Burgess reagent

Burgess reagent

The Burgess reagent or methyl N-carbamate was developed in the laboratory of Edward M. Burgess at Georgia Tech. It is a mild and selective dehydrating reagent often used in organic chemistry. It is used to convert secondary and tertiary alcohol with an adjacent proton into alkenes. Primary alcohols...

) and finally reduced to 8 (sodium cyanoborohydride

Sodium cyanoborohydride

Sodium cyanoborohydride is the inorganic compound with the formula NaBH3. This colourless salt is widely used in organic synthesis for the reduction of imines.-Preparation and use:...

). 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

In 2011, Vanderwal group reported a concise, longest linear sequence of 6 steps, total synthesis of strychnine. It featured a Zincke reaction

Zincke reaction

The Zincke reaction is an organic reaction in which a pyridine is transformed into a pyridinium salt by reaction with 2,4-dinitro-chlorobenzene and a primary amine, named after Theodor Zincke....

followed by an anionic bicyclization reaction and a tandem Brook rearrangement

Brook rearrangement

The Brook rearrangement in organic chemistry is a rearrangement reaction in which a organosilyl group switches position with a hydroxyl proton over a carbon to oxygen covalent bond under the influence of a base . It is named for the Canadian chemist Adrian Gibbs Brook...

/ conjugate addition.

External links

Strychnine Total Syntheses @ SynArchive.com

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