Mukaiyama Aldol-Übersichtsreaktion1
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was a Japanese
organic chemist Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic matter, organic materials, i.e., matter in its various forms that contain ...
. One of the most prolific chemists of the 20th century in the field of
organic synthesis Organic synthesis is a branch of chemical synthesis concerned with the construction of organic compounds. Organic compounds are molecules consisting of combinations of covalently-linked hydrogen, carbon, oxygen, and nitrogen atoms. Within the gen ...
, Mukaiyama helped establish the field of organic chemistry in Japan after World War II.


Education

Mukaiyama studied chemistry at the
Tokyo Institute of Technology The Tokyo Institute of Technology () was a public university in Meguro, Tokyo, Japan. It merged with Tokyo Medical and Dental University to form the Institute of Science Tokyo on 1 October 2024. The Tokyo Institute of Technology was a De ...
, earning his BSc in synthetic organic chemistry in 1948. He became assistant professor at
Gakushuin University is a private university in Mejiro, Toshima, Tokyo. The Gakushūin (or "Peers School") was established during the Meiji period to educate the children of the Japanese nobility, but back then the institution had only the primary and secondary ...
in 1953, where he stayed until he received his Ph.D. in synthetic organic chemistry from the
University of Tokyo The University of Tokyo (, abbreviated as in Japanese and UTokyo in English) is a public research university in Bunkyō, Tokyo, Japan. Founded in 1877 as the nation's first modern university by the merger of several pre-westernisation era ins ...
in 1957.


Research and career


Early work

Mukaiyama became an assistant professor at the
Tokyo Institute of Technology The Tokyo Institute of Technology () was a public university in Meguro, Tokyo, Japan. It merged with Tokyo Medical and Dental University to form the Institute of Science Tokyo on 1 October 2024. The Tokyo Institute of Technology was a De ...
in 1958 and earned his full professorship in 1963. During this time, his main focus was on organophosphorus chemistry. While examining deoxygenation reactions involving phosphines, Mukaiyama found that the mercury(II) acetate employed as a catalyst would react with phosphorus(III) compounds to produce
acetic anhydride Acetic anhydride, or ethanoic anhydride, is the chemical compound with the chemical formula, formula . Commonly abbreviated , it is one the simplest organic acid anhydride, anhydrides of a carboxylic acid and is widely used in the production of c ...
. This initial example expanded into the concept of the redox condensation reaction, in which a weak acid and weak base catalyze a condensation by means of a
redox Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is t ...
reaction – this would become a primary research focus for Mukaiyama for much of his career. In the original reaction, the phosphine served as the reducing agent by accepting oxygen, while the mercury(II) was the oxidation agent that accepted hydrogens, resulting in the condensation of
carboxylic acids In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
with the loss of a molecule of water. This framework was expanded to include the formation of a variety of other functional groups, including
esters In chemistry, an ester is a chemical compound, compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds c ...
and
amides 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 any group, typically organyl groups or hydrogen atoms. The amide group is called a p ...
, but the most significant was the synthesis of phosphoric esters using DEAD and an alcohol in 1967. The same year that paper was published, Mukaiyama's co-author and former student Oyo Mitsunobu attacked the products of the reaction with a
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
in the presence of triphenylphosphine to yield an
ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
, creating what is now known as the
Mitsunobu reaction The Mitsunobu reaction is an organic reaction that converts an alcohol into a variety of functional groups, such as an ester, using triphenylphosphine and an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxy ...
.


Modifications to the aldol reaction

The
aldol reaction The aldol reaction (aldol addition) is a Chemical reaction, reaction in organic chemistry that combines two Carbonyl group, carbonyl compounds (e.g. aldehydes or ketones) to form a new β-hydroxy carbonyl compound. Its simplest form might invol ...
is an essential tool for synthetic chemists. At its simplest, the aldol reaction involves two
carbonyl In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...
compounds which join, forming a carbon-carbon bond. Depending on whether it is performed in acidic or basic conditions, the reaction proceeds by one of the carbonyls attacking the other, which has
tautomer In chemistry, tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the reloca ...
ized into either an enol or enolate. However, when both carbonyls are similar in
pKa In chemistry, an acid dissociation constant (also known as acidity constant, or acid-ionization constant; denoted ) is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction :H ...
they may both function as either the
nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
or the
electrophile In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively Electric charge, charged, have an ...
, meaning the reaction may form either cross-products or self-products. While investigating sulfur-boron compounds in 1971, Mukaiyama reported that the reaction of
ketene In organic chemistry, a ketene is an organic compound of the form , where R and R' are two arbitrary valence (chemistry), monovalent functional group, chemical groups (or two separate Substituent, substitution sites in the same molecule). The na ...
with thioboronite produced a beta-hydroxyalkanethioate via a vinyloxyborane intermediate that would perform an aldol reaction with
formaldehyde Formaldehyde ( , ) (systematic name methanal) is an organic compound with the chemical formula and structure , more precisely . The compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde. It is stored as ...
leftover from the synthesis of ketene. These vinyloxyboranes proved straightforward to synthesize directly from the desired ketones using DBBT, which has a more electron-withdrawing
triflate In organic chemistry, triflate (Preferred IUPAC name, systematic name: trifluoromethanesulfonate), is a functional group with the Chemical formula, formula and Chemical structure, structure . The triflate group is often represented by , as opp ...
group in place of the sulfur. Boron enolates provide an alternative to metal enolates for performing cross-aldol reactions. As an extension of his earlier research with trivalent phosphorus as an oxygen acceptor, Mukaiyama began to examine the role of metallic catalysts for the dehydrative Friedel-Crafts alkylation and in particular titanium(IV) tetrachloride. In 1973, he reported that titanium(IV) chloride treated with
zinc Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...
powder catalyzed a pinacol coupling of carbonyls in THF which formed an
alkene In organic chemistry, an alkene, or olefin, is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or at the terminal position. Terminal alkenes are also known as Alpha-olefin, α-olefins. The Internationa ...
after reflux with 1,4-dioxane. This is what is now known as the McMurry reaction - McMurry published a year later and cited both Mukaiyama and the group of Tyrlik in Poland in his paper, but Japan's position in the international organic chemistry community was not yet fully developed and the naming persists. Mukaiyama again turned to titanium(IV) chloride while seeking an appropriate
Lewis acid A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any ...
to activate aldehydes for reaction with silyl enol ethers in what became known as the Mukaiyama aldol reaction. Published in 1973 as Mukaiyama was in the process of migrating to the
University of Tokyo The University of Tokyo (, abbreviated as in Japanese and UTokyo in English) is a public research university in Bunkyō, Tokyo, Japan. Founded in 1877 as the nation's first modern university by the merger of several pre-westernisation era ins ...
, it is a cross-aldol reaction between a silyl enol ether (typically derived from a carbonyl of choice using the method of
Stork Storks are large, long-legged, long-necked wading birds with long, stout bills. They belong to the family Ciconiidae, and make up the order Ciconiiformes . Ciconiiformes previously included a number of other families, such as herons and ibise ...
) and an aldehyde of choice in the presence of a Lewis acid like titanium(IV) chloride. The reaction is a landmark case on how activating aldehydes can allow even electronically neutral and weakly nucleophilic compounds like silyl enol ethers to be used as reagents. A Lewis acid must be added to use silyl enol ethers but not boron enolates because boron has an empty orbital but silicon does not, allowing boron to act as an electron acceptor. Tin(II) goes a step further by having multiple empty orbitals, allowing it to coordinate
chiral Chirality () is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek language, Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is dist ...
ligands In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...
and induce
enantioselectivity In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non- stereospecific creation of a new stereocenter or during a non-stereospecific transformation o ...
. In 1982 Mukaiyama showed that tin(II) enolates formed from tin(II) triflate could produce aldol products that were over 95% stereospecific. In a time when asymmetric reactions largely relied on chiral auxiliaries to be covalently bound to the reactants, tin(II) enolates formed from chiral diamine ligands derived from
L-proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the Protein biosynthesis, biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine n ...
could achieve over 90% ee.


Namesake reagent

In 1975, Mukaiyama reported that ''N''-methyl-2-chloropyridinium iodide (also called 2-chloro-1-methylpyridinium iodide) allowed for a dehydration condensation between a
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
and an
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
or similar functional groups to form an
ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
linkage. In the initial stage of the process, the carboxyl displaces the
halogen The halogens () are a group in the periodic table consisting of six chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and the radioactive elements astatine (At) and tennessine (Ts), though some authors would ...
atom on the reagent in the presence of a base. The resulting pyridyl ester is an activated
electrophile In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively Electric charge, charged, have an ...
and also serves as a good
leaving group In organic chemistry, a leaving group typically means a Chemical species, molecular fragment that departs with an electron, electron pair during a reaction step with heterolysis (chemistry), heterolytic bond cleavage. In this usage, a ''leaving gr ...
in a subsequent
nucleophilic acyl substitution In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen atom and an organyl group () or hydrogen in the case of formyl group ( ...
reaction with the alcohol reactant as
nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
. Thus, the family of 2-halo-''N''-alkylpyridinium salts are named the Mukaiyama reagents. The reaction gives low yields if there are sterically large groups adjacent to the site of the reaction, such as tertiary carbons, but can be improved by using
bromine Bromine is a chemical element; it has chemical symbol, symbol Br and atomic number 35. It is a volatile red-brown liquid at room temperature that evaporates readily to form a similarly coloured vapour. Its properties are intermediate between th ...
as the halogen. In the years since its discovery, a number of different onium salts of aza- arenes have been used to catalyze a number of different dehydration reactions, including a macrolactonization. In 1994, Isamu Shiina developed his namesake macrolactonization in the Mukaiyama lab, making use of an
aromatic In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated system, conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugati ...
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
anhydride An acid anhydride is a type of chemical compound derived by the removal of water molecules from an acid (chemistry), acid. In organic chemistry, organic acid anhydrides contain the functional group . Organic acid anhydrides often form when one ...
in the presence of a
Lewis acid A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any ...
catalyst.


Taxol synthesis

In the early 1990s, at least thirty separate groups were working on the total synthesis of the chemotherapy medicine
paclitaxel Paclitaxel, sold under the brand name Taxol among others, is a chemotherapy medication used to treat ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. It is administered b ...
(Taxol), culminating with the groups of Robert A. Holton and K. C. Nicolaou publishing nearly simultaneously in 1994. By then, Mukaiyama had retired from the
University of Tokyo The University of Tokyo (, abbreviated as in Japanese and UTokyo in English) is a public research university in Bunkyō, Tokyo, Japan. Founded in 1877 as the nation's first modern university by the merger of several pre-westernisation era ins ...
after reaching the mandatory age of 60 and set up an academic lab at the Tokyo University of Science. The Mukaiyama taxol total synthesis was published between the years of 1997 and 1999 after five years of research, making the Mukaiyama lab the sixth group to report results. This total synthesis is largely a linear synthesis which forms the four rings of taxol in the order C, B, A, D. It is differentiated from the others from its use of L-serine as a starting material and for being the only total synthesis not to use the Ojima lactam to create the amide tail. Instead, the tail is created from scratch by converting benzyloxyacetic acid into a
silyl enol ether In organosilicon chemistry, silyl enol ethers are a class of organic compounds that share the common functional group , composed of an enolate () bonded to a silane () through its oxygen end and an ethene group () as its carbon end. They are i ...
, joining it with benzaldehyde with a Mukaiyama aldol addition, and creating the amide from the alcohol via a
Mitsunobu reaction The Mitsunobu reaction is an organic reaction that converts an alcohol into a variety of functional groups, such as an ester, using triphenylphosphine and an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxy ...
followed by benzoylation. The synthesis also made use of three Swern oxidations during the synthesis of the C ring. This reaction is typically performed at very low temperatures (< -50 °C) to stabilize its activated
DMSO Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula . This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is ...
intermediate and constantly evolves the strong-smelling DMS, making it very difficult to work with at large scales. The difficulties encountered during their total synthesis prompted Mukaiyama to pursue an alternative method, and in 2001 a room-temperature oxidation involving N-chlorosuccinimide and a catalytic amount of N-t-butylbenzenesulfenamide was developed. The more
electronegative Electronegativity, symbolized as , is the tendency for an atom of a given chemical element to attract shared electrons (or electron density) when forming a chemical bond. An atom's electronegativity is affected by both its atomic number and the d ...
nitrogen adjacent to the sulfur in the sulfenamide increased the stability of the intermediate relative to that formed from the sulfur-carbon bond of DMSO and was inspired by his earlier work with sulfenamides while still at the Tokyo Institute of Technology.


Legacy

Mukaiyama had a scientific career spanning over sixty years, during which he published over 900 papers. After its founding in 1972, Mukaiyama only published in the Japanese journal '' Chemistry Letters'', citing a belief that "the results of one's chemistry should be published in journals of one's country." The combination of the high quality of his work and the over 600 papers that he published in ''Chemistry Letters'' played an important role in its spread to other nations. A total of 145 people earned their doctorates under Mukaiyama, with 54 eventually becoming professors in various institutions.


Honors and awards

Mukaiyama has been recognized for his achievements in the form of seven honorary degrees and membership in the national academies of four nations. He is the namesake of the Mukaiyama Award, awarded by the Society of Synthetic Organic Chemistry, Japan since 2005. His major awards include: * Chemical Society of Japan Award in 1973 * Imperial Prize and Academy Prize from the
Japan Academy The Japan Academy ( Japanese: 日本学士院, ''Nihon Gakushiin'') is an honorary organisation and science academy founded in 1879 to bring together leading Japanese scholars with distinguished records of scientific achievements. The Academy is ...
in 1983 * Nicholaus Copernicus Medal from the
Polish Academy of Sciences The Polish Academy of Sciences (, PAN) is a Polish state-sponsored institution of higher learning. Headquartered in Warsaw, it is responsible for spearheading the development of science across the country by a society of distinguished scholars a ...
in 1986 *
Person of Cultural Merit is an official Japanese recognition and honour which is awarded annually to select people who have made outstanding cultural contributions. This distinction is intended to play a role as a part of a system of support measures for the promotion of ...
from Japan in 1992 * Chevalier de l’Ordre National du Mérite from France in 1994 * ACS Award for Creative work in Synthetic Organic Chemistry from the
American Chemical Society The American Chemical Society (ACS) is a scientific society based in the United States that supports scientific inquiry in the field of chemistry. Founded in 1876 at New York University, the ACS currently has more than 155,000 members at all ...
in 1996 *
Order of Culture The is a Japanese Order (decoration), order, established on February 11, 1937. The order has one class only, and may be awarded to men and women for contributions to Japanese Art, Japan's art, Japanese Literature, literature, science, technolog ...
from Japan in 1997 * Tetrahedron Prize for Creativity in Organic Chemistry from
Elsevier Elsevier ( ) is a Dutch academic publishing company specializing in scientific, technical, and medical content. Its products include journals such as ''The Lancet'', ''Cell (journal), Cell'', the ScienceDirect collection of electronic journals, ...
in 1998 * Sir Derek Barton Gold Medal from the
Royal Society of Chemistry The Royal Society of Chemistry (RSC) is a learned society and professional association in the United Kingdom with the goal of "advancing the chemistry, chemical sciences". It was formed in 1980 from the amalgamation of the Chemical Society, the ...
in 1998


References

{{DEFAULTSORT:Mukaiyama, Teruaki 1927 births 2018 deaths People from Nagano (city) Tokyo Institute of Technology alumni University of Tokyo alumni Academic staff of Tokyo Institute of Technology Japanese organic chemists 20th-century Japanese chemists 21st-century Japanese chemists Scientists from Nagano Prefecture