Quinine Total Synthesis
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total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes i ...
of
quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to '' Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg ...
, a naturally-occurring antimalarial drug, was developed over a 150-year period. The development of synthetic quinine is considered a milestone in
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clay ...
although it has never been produced industrially as a substitute for natural occurring quinine. The subject has also been attended with some controversy: Gilbert Stork published the first stereoselective total synthesis of quinine in 2001, meanwhile shedding doubt on the earlier claim by
Robert Burns Woodward Robert Burns Woodward (April 10, 1917 – July 8, 1979) was an American organic chemist. He is considered by many to be the most preeminent synthetic organic chemist of the twentieth century, having made many key contributions to the subject, e ...
and William Doering in 1944, claiming that the final steps required to convert their last synthetic intermediate, quinotoxine, into quinine would not have worked had Woodward and Doering attempted to perform the experiment. A 2001 editorial published in ''
Chemical & Engineering News ''Chemical & Engineering News'' (''C&EN'') is a weekly news magazine published by the American Chemical Society, providing professional and technical news and analysis in the fields of chemistry and chemical engineering.quinoline Quinoline is a heterocyclic aromatic organic compound with the chemical formula C9H7N. It is a colorless hygroscopic liquid with a strong odor. Aged samples, especially if exposed to light, become yellow and later brown. Quinoline is only ...
with a
methoxy In organic chemistry, a methoxy group is the functional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula . On a benzene ring, the Hammett equation classifies a methoxy substituent at the ''para'' position ...
substituent. The
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent su ...
component has a
quinuclidine Quinuclidine is an organic compound and a bicyclic amine and used as a catalyst and a chemical building block. It is a strong base with p''K''a of the conjugate acid of 11.0.{{cite journal , title=Azatriquinanes: Synthesis, Structure, and Reacti ...
skeleton and the
methylene bridge In organic chemistry, a methylene bridge, methylene spacer, or methanediyl group is any part of a molecule with formula ; namely, a carbon atom bound to two hydrogen atoms and connected by single bonds to two other distinct atoms in the rest of ...
in between the two components has a
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydrox ...
group. The substituent at the 3 position is a
vinyl group In organic chemistry, a vinyl group (abbr. Vi; IUPAC name: ethenyl group) is a functional group with the formula . It is the ethylene (IUPAC name: ethene) molecule () with one fewer hydrogen atom. The name is also used for any compound contai ...
. The molecule is
optically active Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circular ...
with five
stereogenic In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups cr ...
centers (the N1 and C4 constituting a single asymmetric unit), making synthesis potentially difficult because it is one of 16
stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms i ...
s.


Quinine total synthesis timeline

* 1817: First isolation of quinine from
cinchona ''Cinchona'' (pronounced or ) is a genus of flowering plants in the family Rubiaceae containing at least 23 species of trees and shrubs. All are native to the tropical Andean forests of western South America. A few species are reportedly natu ...
tree by Pierre Joseph Pelletier and Joseph Caventou. * 1853:
Louis Pasteur Louis Pasteur (, ; 27 December 1822 – 28 September 1895) was a French chemist and microbiologist renowned for his discoveries of the principles of vaccination, microbial fermentation and pasteurization, the latter of which was named after ...
obtains quinotoxine (or ''quinicine'' in older literature) by acid-catalysed
isomerization In chemistry, isomerization or isomerisation is the process in which a molecule, polyatomic ion or molecular fragment is transformed into an isomer with a different chemical structure. Enolization is an example of isomerization, as is tautome ...
of quinine. : * 1856: Sir
William Henry Perkin Sir William Henry Perkin (12 March 1838 – 14 July 1907) was a British chemist and entrepreneur best known for his serendipitous discovery of the first commercial synthetic organic dye, mauveine, made from aniline. Though he failed in trying ...
attempts quinine synthesis by oxidation of ''N''-allyl
toluidine There are three isomers of toluidine, which are organic compounds. These isomers are ''o''-toluidine, ''m''-toluidine, and ''p''-toluidine, with the prefixed letter abbreviating, respectively, ''ortho''; ''meta''; and ''para''. All three are aryl ...
based on the erroneous idea that two equivalents of this compound with
chemical formula In chemistry, a chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, ...
C10H13N plus three equivalents of oxygen yield one equivalent of C20H24N2O2 (quinine's chemical formula) and one equivalent of water. His oxidations with other toluidines sets him on the path to discover mauveine. The commercial importance of mauveine eventually lead to the birth of the chemical industry. : * 1907: the correct atom connectivity established by Paul Rabe. * 1918: Paul Rabe and Karl Kindler synthesize quinine from quinotoxine, reversing the Pasteur chemistry. The lack of experimental details in this publication would become a major issue in the Stork–Woodward controversy almost a century later. : :The first step in this sequence is sodium hypobromite addition to quinotoxine to an ''N''-bromo intermediate possibly with structure 2. The second step is
organic oxidation Organic reductions or organic oxidations or organic redox reactions are redox reactions that take place with organic compounds. In organic chemistry oxidations and reductions are different from ordinary redox reactions, because many reactions car ...
with
sodium ethoxide Sodium ethoxide, also referred to as sodium ethylate, is the ionic, organic compound with the formula , or NaOEt (Et = ethane). It is a white solid, although impure samples appear yellow or brown. It dissolves in polar solvents such as ethanol. ...
in
ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a h ...
. Because of the basic conditions the initial product quininone interconverts with quinidinone via a common
enol In organic chemistry, alkenols (shortened to enols) are a type of reactive structure or intermediate in organic chemistry that is represented as an alkene (olefin) with a hydroxyl group attached to one end of the alkene double bond (). The te ...
intermediate and
mutarotation Mutarotation is the change in the ''optical rotation'' because of the change in the equilibrium between two anomers, when the corresponding stereocenters interconvert. Cyclic sugars show mutarotation as α and β anomeric forms interconvert. The op ...
is observed. In the third step the
ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bon ...
group is reduced with
aluminum Aluminium (aluminum in American and Canadian English) is a chemical element with the symbol Al and atomic number 13. Aluminium has a density lower than those of other common metals, at approximately one third that of steel. It h ...
powder and sodium ethoxide in ethanol and quinine can be identified. Quinotoxine is the first relay molecule in the Woodward/Doering claim. : * 1939: Rabe and Kindler re investigate a sample left over from their 1918 experiments and identify and isolate quinine (again) together with
diastereomer In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have dif ...
s quinidine, epi-quinine and epi-quinidine. * 1940:
Robert Burns Woodward Robert Burns Woodward (April 10, 1917 – July 8, 1979) was an American organic chemist. He is considered by many to be the most preeminent synthetic organic chemist of the twentieth century, having made many key contributions to the subject, e ...
signs on as a consultant for the
Polaroid Corporation Polaroid is an American company best known for its instant film and cameras. The company was founded in 1937 by Edwin H. Land, to exploit the use of its Polaroid polarizing polymer. Land ran the company until 1981. Its peak employment was 21,0 ...
at the request of
Edwin H. Land Edwin Herbert Land, ForMemRS, FRPS, Hon.MRI (May 7, 1909 – March 1, 1991) was an Russian-American scientist and inventor, best known as the co-founder of the Polaroid Corporation. He invented inexpensive filters for polarizing light, a ...
. Quinine is of interest to Polaroid for its light polarizing properties. * 1943: Prelog and Proštenik interconvert an allyl
piperidine Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic compound, heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless ...
called homomeroquinene and quinotoxine. Homomeroquinene (the second relay molecule in the Woodward/Doering claim) is obtained in several steps from the
biomolecule A biomolecule or biological molecule is a loosely used term for molecules present in organisms that are essential to one or more typically biological processes, such as cell division, morphogenesis, or development. Biomolecules include larg ...
cinchonine (related to quinidine but without the
methoxy In organic chemistry, a methoxy group is the functional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula . On a benzene ring, the Hammett equation classifies a methoxy substituent at the ''para'' position ...
group): : :The key step in the assembly of quinotoxine is a
Claisen condensation The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β- diketone. It is named after Ra ...
: : * 1944:
Robert Burns Woodward Robert Burns Woodward (April 10, 1917 – July 8, 1979) was an American organic chemist. He is considered by many to be the most preeminent synthetic organic chemist of the twentieth century, having made many key contributions to the subject, e ...
and
W. E. Doering W. may refer to: * SoHo (Australian TV channel) (previously W.), an Australian pay television channel * ''W.'' (film), a 2008 American biographical drama film based on the life of George W. Bush * "W.", the fifth track from Codeine's 1992 EP ''Bar ...
report the synthesis of quinine, starting from 7-hydroxy isoquinoline. Although the title of their one-page publication is ''The total synthesis of quinine'' it is oddly not the synthesis of quinine but that of the precursor homomeroquinene (racemic) and then with groundwork already provided by Prelog a year earlier to quinotoxine (enantiopure after
chiral resolution Chiral resolution, or enantiomeric resolution, is a process in stereochemistry for the separation of racemic compounds into their enantiomers. It is an important tool in the production of optically active compounds, including drugs. Another term ...
) that is described. : :Woodward and Doering argue that Rabe in 1918 already proved that this compound will eventually give quinine but do not repeat Rabe's work. In this project 27-year-old assistant professor Woodward is the theorist and postdoc Doering (age 26) the bench worker. According to William, Bob was able to boil water but an egg would be a challenge. As many natural quinine resources were tied up in the enemy-held Dutch East Indies, synthetic quinine was a promising alternative for fighting malaria on the battlefield and both men become instant war heroes making headlines in the ''
New York Times ''The New York Times'' (''the Times'', ''NYT'', or the Gray Lady) is a daily newspaper based in New York City with a worldwide readership reported in 2020 to comprise a declining 840,000 paid print subscribers, and a growing 6 million paid ...
'', ''
Newsweek ''Newsweek'' is an American weekly online news magazine co-owned 50 percent each by Dev Pragad, its president and CEO, and Johnathan Davis, who has no operational role at ''Newsweek''. Founded as a weekly print magazine in 1933, it was widely ...
'' and ''
Life Life is a quality that distinguishes matter that has biological processes, such as Cell signaling, signaling and self-sustaining processes, from that which does not, and is defined by the capacity for Cell growth, growth, reaction to Stimu ...
''. * 1944: The then 22-year-old Gilbert Stork writes to Woodward asking him if he did repeat Rabe's work. * 1945: Woodward and Doering publish their second lengthy quinine paper. One of the two referees rejects the manuscript (too much historic material, too much experimental details and poor literary style with inclusion of words like ''adumbrated'' and ''apposite'') but it is published without changes nonetheless. * 1974: Kondo and Mori synthesize
racemic In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
vinylic gamma-
lactone Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. Lactones are formed by intramolecular esterification of the co ...
,s a key starting material in Stork's 2001 quinine synthesis. :: :The starting materials are
trans-2-butene-1,4-diol Trans- is a Latin prefix meaning "across", "beyond", or "on the other side of". Used alone, trans may refer to: Arts, entertainment, and media * Trans (festival), a former festival in Belfast, Northern Ireland, United Kingdom * ''Trans'' (film ...
and
ethyl orthoacetate Triethyl orthoacetate is the organic compound with the formula CH3C(OC2H5)3. It is the ethyl orthoester of acetic acid. It is a colorless oily liquid. Triethyl orthoacetate is used in organic synthesis for acetylation. It is also used in the Jo ...
and the key step is a
Claisen rearrangement The Claisen rearrangement is a powerful carbon–carbon bond-forming chemical reaction discovered by Rainer Ludwig Claisen. The heating of an allyl vinyl ether will initiate a ,3sigmatropic rearrangement to give a γ,δ-unsaturated carbonyl, ...
* 1988: Ishibashi & Taniguchy resolve said lactone to enantiopure compounds via
chiral resolution Chiral resolution, or enantiomeric resolution, is a process in stereochemistry for the separation of racemic compounds into their enantiomers. It is an important tool in the production of optically active compounds, including drugs. Another term ...
: : :In this process the racemic lactone reacts in aminolysis with (''S'')- methylbenzylamine assisted by
triethylaluminum Triethylaluminium is one of the simplest examples of an organoaluminium compound. Despite its name it has the formula Al2( C2H5)6 (abbreviated as Al2Et6 or TEA), as it exists as a dimer. This colorless liquid is pyrophoric. It is an industrial ...
to a
diastereomeric pair In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have dif ...
of
amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...
s which can be separated by
column chromatography Column chromatography in chemistry is a chromatography method used to isolate a single chemical compound from a mixture. Chromatography is able to separate substances based on differential adsorption of compounds to the adsorbent; compounds move t ...
. The ''S''-enantiomer is converted back to the ''S''-lactone in two steps by hydrolysis with
potassium hydroxide Potassium hydroxide is an inorganic compound with the formula K OH, and is commonly called caustic potash. Along with sodium hydroxide (NaOH), KOH is a prototypical strong base. It has many industrial and niche applications, most of which expl ...
and
ethylene glycol Ethylene glycol ( IUPAC name: ethane-1,2-diol) is an organic compound (a vicinal diol) with the formula . It is mainly used for two purposes, as a raw material in the manufacture of polyester fibers and for antifreeze formulations. It is an od ...
followed by azeotropic ring closure. * 2001: Gilbert Stork publishes his stereoselective quinine synthesis. He questions the validity of the Woodward/Doering claim: "the basis of their characterization of Rabe’s claim as “established” is unclear". M. Jacobs, writing in The
Chemical & Engineering News ''Chemical & Engineering News'' (''C&EN'') is a weekly news magazine published by the American Chemical Society, providing professional and technical news and analysis in the fields of chemistry and chemical engineering.alkaloid Alkaloids are a class of basic BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Th ...
chemist, that he had ample opportunity to compare his quinine reaction product with authentic samples and that the described 1918 chemistry was repeated by Rabe although not with quinotoxine itself but still with closely related derivatives. * 2008: Smith and Williams revisit and confirm Rabe's ''d''-quinotoxine to quinine route. : * 2018:
Nuno Maulide Nuno Maulide (born 1979, Lisboa, Portugal), is a Portuguese chemist and scientist, currently professor of organic chemistry at the University of Vienna, as well as a science-related writer and speaker. He is also an amateur pianist. Son of a Mozamb ...
and his team report the total synthesis of quinine via C–H activation, including analogues with improved antimalarial activity''C–H Activation Enables a Concise Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity'' D. H. O'Donovan et al Angewandte Chemie International Edition 2018


Stork quinine total synthesis

The Stork quinine synthesis starts from chiral (''S'')-4-vinylbutyrolactone 1. The compound is obtained by
chiral resolution Chiral resolution, or enantiomeric resolution, is a process in stereochemistry for the separation of racemic compounds into their enantiomers. It is an important tool in the production of optically active compounds, including drugs. Another term ...
and in fact, in the subsequent steps all stereogenic centers are put in place by
chiral induction In stereochemistry, asymmetric induction (also enantioinduction) describes the preferential formation in a chemical reaction of one enantiomer or diastereoisomer over the other as a result of the influence of a chiral feature present in the sub ...
: the sequence does not contain
asymmetric Asymmetric may refer to: *Asymmetry in geometry, chemistry, and physics Computing * Asymmetric cryptography, in public-key cryptography *Asymmetric digital subscriber line, Internet connectivity * Asymmetric multiprocessing, in computer architect ...
steps. The
lactone Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. Lactones are formed by intramolecular esterification of the co ...
is ring-opened with
diethylamine Diethylamine is an organic compound with the formula (CH3CH2)2NH. It is a secondary amine. It is a flammable, weakly alkaline liquid that is miscible with most solvents. It is a colorless liquid, but commercial samples often appear brown due to im ...
to
amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...
2 and its
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydrox ...
group is protected as a ''tert''-butyldimethyl
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 protectin ...
(TBS) in 3. The C5 and C6 atoms are added as ''tert''-butyldiphenylsilyl (TBDPS) protected iodoethanol in a
nucleophilic substitution In chemistry, a nucleophilic substitution is a class of chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass c ...
of acidic C4 with lithium diisopropylamide (LDA) at −78 °C to 4 with correct stereochemistry. Removal of the silyl protecting group with ''p''-toluenesulfonic acid to
alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
4b and ring-closure by azeotropic distillation returns the compound to lactone 5 (direct
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 (or their equivalents). Alkylating agents are reagents for effectin ...
of 1 met with undisclosed problems). The lactone is then reduced to the
lactol In organic chemistry, a lactol is the cyclic equivalent of a hemiacetal or a hemiketal. The compound is formed by the intramolecular nucleophilic addition of a hydroxyl group to the carbonyl group of an aldehyde or a ketone. A lactol is often ...
5b with diisobutylaluminum hydride and its liberated
aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl group ...
reacts in a
Wittig reaction The Wittig reaction or Wittig olefination is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide called a Wittig reagent. Wittig reactions are most commonly used to convert aldehydes and ketones to alkenes. Most ...
with methoxymethylenetriphenylphosphine (delivering the C8 atom) to form
enol ether In organic chemistry an enol ether is an alkene with an alkoxy substituent. The general structure is R2C=CR-OR where R = H, alkyl or aryl. A common subfamily of enol ethers are vinyl ethers, with the formula ROCH=CH2. Important enol ethers includ ...
6. The hydroxyl group is replaced in a Mitsunobu reaction by an
azide In chemistry, azide is a linear, polyatomic anion with the formula and structure . It is the conjugate base of hydrazoic acid . Organic azides are organic compounds with the formula , containing the azide functional group. The dominant ...
group with diphenylphosphoryl azide in 7 and acid hydrolysis yields the azido aldehyde 8. The methyl group in ''6-methoxy-4-methylquinoline'' 9 is sufficiently
acidic In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a s ...
for
nucleophilic addition In organic chemistry, a nucleophilic addition reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic additions ...
of its anion (by reaction with LDA) to the aldehyde group in 8 to form 10 as a mixture of
epimer In stereochemistry, an epimer is one of a pair of diastereomers. The two epimers have opposite configuration at only one stereogenic center out of at least two. All other stereogenic centers in the molecules are the same in each. Epimerization is ...
s. This is of no consequence for stereocontrol because in the next step the alcohol is oxidized in a Swern oxidation to
ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bon ...
11. A
Staudinger reaction The Staudinger reaction is a chemical reaction of an organic azide with a phosphine or phosphite produces an iminophosphorane. The reaction was discovered by and named after Hermann Staudinger. The reaction follows this stoichiometry: :R3P + R ...
with
triphenylphosphine Triphenylphosphine (IUPAC name: triphenylphosphane) is a common organophosphorus compound with the formula P(C6H5)3 and often abbreviated to P Ph3 or Ph3P. It is widely used in the synthesis of organic and organometallic compounds. PPh3 exists ...
closes the ring between the ketone and the azide to the tetrahydropyridine 12. The
imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...
group in this compound is reduced to the
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent su ...
13 with
sodium borohydride Sodium borohydride, also known as sodium tetrahydridoborate and sodium tetrahydroborate, is an inorganic compound with the formula Na BH4. This white solid, usually encountered as an aqueous basic solution, is a reducing agent that finds applic ...
with the correct
stereospecific In chemistry, stereospecificity is the property of a reaction mechanism that leads to different stereoisomeric reaction products from different stereoisomeric reactants, or which operates on only one (or a subset) of the stereoisomers."Overlap Con ...
ity. The silyl protecting group is removed with hydrogen fluoride to alcohol 14 and then activated as a mesyl
leaving group In chemistry, a leaving group is defined by the IUPAC as an atom or group of atoms that detaches from the main or residual part of a substrate during a reaction or elementary step of a reaction. However, in common usage, the term is often limited ...
by reaction with
mesyl chloride Methanesulfonyl chloride (mesyl chloride) is an organosulfur compound with the formula . Using the organic pseudoelement symbol Ms for the methanesulfonyl (or mesyl) group –, it is frequently abbreviated MsCl in reaction schemes or equations. I ...
in
pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakl ...
which enables the third ring closure to 15. In the final step the C9 hydroxyl group was introduced by oxidation with
sodium hydride Sodium hydride is the chemical compound with the empirical formula Na H. This alkali metal hydride is primarily used as a strong yet combustible base in organic synthesis. NaH is a saline (salt-like) hydride, composed of Na+ and H− ions, in ...
,
dimethylsulfoxide Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula ( CH3)2. This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds a ...
and oxygen with quinine to epiquinine ratio of 14:1.


Woodward–Doering formal quinine total synthesis

The 1944 Woodward–Doering synthesis starts from 7-hydroxyisoquinoline 3 for the
quinuclidine Quinuclidine is an organic compound and a bicyclic amine and used as a catalyst and a chemical building block. It is a strong base with p''K''a of the conjugate acid of 11.0.{{cite journal , title=Azatriquinanes: Synthesis, Structure, and Reacti ...
skeleton which is somewhat counter intuitive because one goes from a stable heterocyclic aromatic system to a completely saturated bicyclic ring. This compound (already known since 1895) is prepared in two steps. The first reaction step is
condensation reaction In organic chemistry, a condensation reaction is a type of chemical reaction in which two molecules are combined to form a single molecule, usually with the loss of a small molecule such as water. If water is lost, the reaction is also known as a ...
of
3-hydroxybenzaldehyde 3-Hydroxybenzaldehyde is an organic compound with the formula . It is a colorless solid although most samples appear tan. Two other isomers of hydroxybenzaldehyde exist. Preparation It has been prepared from 3-nitrobenzaldehyde in a sequence o ...
1 with (formally) the di
acetal In organic chemistry, an acetal is a functional group with the connectivity . Here, the R groups can be organic fragments (a carbon atom, with arbitrary other atoms attached to that) or hydrogen, while the R' groups must be organic fragment ...
of aminoacetaldehyde to the
imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...
2 and the second reaction step is cyclization in concentrated sulfuric acid. Isoquinoline 3 is then alkylated in another condensation by
formaldehyde Formaldehyde ( , ) ( systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section ...
and
piperidine Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic compound, heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless ...
and the product is isolated as the sodium salt of 4.
Hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate org ...
at 220 °C for 10 hours in methanol with
sodium methoxide Sodium methoxide is the simplest sodium alkoxide. With the formula , it is a white solid, which is formed by the deprotonation of methanol. Itis a widely used reagent in industry and the laboratory. It is also a dangerously caustic base. ...
liberates the piperidine group and leaving the methyl group in 5 with already all carbon and nitrogen atoms accounted for. A second
hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate org ...
takes place with
Adams catalyst Adams' catalyst, also known as platinum dioxide, is usually represented as platinum(IV) oxide Water of crystallization, hydrate, PtO2•H2O. It is a catalyst for hydrogenation and hydrogenolysis in organic synthesis. This dark brown powder is comm ...
in
acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main componen ...
to ''tetrahydroisoquinoline'' 6. Further hydrogenation does not take place until the amino group is acylated with
acetic anhydride Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula (CH3CO)2O. Commonly abbreviated Ac2O, it is the simplest isolable anhydride of a carboxylic acid and is widely used as a reagent in organic synthesis. It is a c ...
in methanol but by then 7 is again hydrogenated with Raney nickel in
ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a h ...
at 150 °C under high pressure to ''decahydroisoquinoline'' 8. The mixture of ''cis'' and ''trans'' isomers is then oxidized by
chromic acid The term chromic acid is usually used for a mixture made by adding concentrated sulfuric acid to a dichromate, which may contain a variety of compounds, including solid chromium trioxide. This kind of chromic acid may be used as a cleaning mixt ...
in acetic acid to the
ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bon ...
9. Only the cis isomer crystallizes and used in the next reaction step, a ring opening with the
alkyl nitrite In organic chemistry, alkyl nitrites are a group of organic compounds based upon the molecular structure , where R represents an alkyl group. Formally they are alkyl esters of nitrous acid. They are distinct from nitro compounds (). The first ...
''ethyl nitrite'' with
sodium ethoxide Sodium ethoxide, also referred to as sodium ethylate, is the ionic, organic compound with the formula , or NaOEt (Et = ethane). It is a white solid, although impure samples appear yellow or brown. It dissolves in polar solvents such as ethanol. ...
in
ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a h ...
to 10 with a newly formed
carboxylic ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glyceride ...
group and an
oxime In organic chemistry, an oxime is a organic compound belonging to the imines, with the general formula , where R is an organic side-chain and R’ may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substitu ...
group. The oxime group is hydrogenated to the
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent su ...
11 with
platinum Platinum is a chemical element with the symbol Pt and atomic number 78. It is a dense, malleable, ductile, highly unreactive, precious, silverish-white transition metal. Its name originates from Spanish , a diminutive of "silver". Pla ...
in
acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main componen ...
and
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 (or their equivalents). Alkylating agents are reagents for effectin ...
with iodomethane gives the
quaternary ammonium salt In chemistry, quaternary ammonium cations, also known as quats, are positively charged polyatomic ions of the structure , R being an alkyl group or an aryl group. Unlike the ammonium ion () and the primary, secondary, or tertiary ammonium cat ...
12 and subsequently the betaine 13 after reaction with
silver oxide Silver oxide is the chemical compound with the formula Ag2O. It is a fine black or dark brown powder that is used to prepare other silver compounds. Preparation Silver oxide can be prepared by combining aqueous solutions of silver nitrate and ...
. Quinine's
vinyl group In organic chemistry, a vinyl group (abbr. Vi; IUPAC name: ethenyl group) is a functional group with the formula . It is the ethylene (IUPAC name: ethene) molecule () with one fewer hydrogen atom. The name is also used for any compound contai ...
is then constructed by
Hofmann elimination Hofmann elimination is an elimination reaction of an amine to form alkenes. The least stable alkene (the one with the least number of substituents on the carbons of the double bond), called the Hofmann product, is formed. This tendency, known as ...
with
sodium hydroxide Sodium hydroxide, also known as lye and caustic soda, is an inorganic compound with the formula NaOH. It is a white solid ionic compound consisting of sodium cations and hydroxide anions . Sodium hydroxide is a highly caustic base and alkal ...
in water at 140 °C. This process is accompanied by
hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...
of both the ester and the amide group but it is not the free amine that is isolated but the
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
14 by reaction with
potassium cyanate Potassium cyanate is an inorganic compound with the formula KOCN (sometimes denoted KCNO). It is a colourless solid. It is used to prepare many other compounds including useful herbicide. Worldwide production of the potassium and sodium salts w ...
. In the next step the
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyl ...
group is
ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...
ified with ethanol and the urea group replaced with a
benzoyl In organic chemistry, benzoyl (, ) is the functional group with the formula C6H5CO-. It can be viewed as benzaldehyde missing one hydrogen. The term "benzoyl" should not be confused with benzyl, which has the formula C6H5CH2. The benzoyl grou ...
group. The final step is a
claisen condensation The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β- diketone. It is named after Ra ...
of 15 with ethyl quininate 16, which after acidic workup yields
racemic In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
quinotoxine 17. The desired enantiomer is obtained by
chiral resolution Chiral resolution, or enantiomeric resolution, is a process in stereochemistry for the separation of racemic compounds into their enantiomers. It is an important tool in the production of optically active compounds, including drugs. Another term ...
with the chiral dibenzoyl ester of
Tartaric acid Tartaric acid is a white, crystalline organic acid that occurs naturally in many fruits, most notably in grapes, but also in bananas, tamarinds, and citrus. Its salt Salt is a mineral composed primarily of sodium chloride (NaCl), a c ...
. The conversion of this compound to quinine is based on the Rabe–Kindler chemistry discussed in the timelime.


External links


Quinine Total Syntheses @ SynArchive.com
* Quinine story at Harvard.ed
Link


References

{{reflist Total synthesis Quinine