was a Japanese
organic chemist
Organic chemistry is a subdiscipline within chemistry involving the 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.Clayden, J.; ...
. One of the most prolific chemists of the 20th century in the field of
organic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than inorganic compounds, and their synthesis has developed into one o ...
, Mukaiyama helped establish the field of organic chemistry in Japan after World War II.
[
]
Education
Mukaiyama studied chemistry at the
Tokyo Institute of Technology
is a national research university located in Greater Tokyo Area, Japan. Tokyo Tech is the largest institution for higher education in Japan dedicated to science and technology, one of first five Designated National University and selected a ...
, earning his BSc in synthetic organic chemistry in 1948. He became assistant professor at
Gakushuin University
is a private university in Mejiro, Toshima Ward, Tokyo. It was re-established after World War II as an affiliate of the Gakushūin School Corporation. The privatized successor to the original Gakushūin University (or "Peers School") was establ ...
in 1953, where he stayed until he received his Ph.D. in synthetic organic chemistry from the
University of Tokyo
, abbreviated as or UTokyo, is a public research university located in Bunkyō, Tokyo, Japan. Established in 1877, the university was the first Imperial University and is currently a Top Type university of the Top Global University Project by ...
in 1957.
Research and career
Early work
Mukaiyama became an assistant professor at the
Tokyo Institute of Technology
is a national research university located in Greater Tokyo Area, Japan. Tokyo Tech is the largest institution for higher education in Japan dedicated to science and technology, one of first five Designated National University and selected a ...
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
Phosphine (IUPAC name: phosphane) is a colorless, flammable, highly toxic compound with the chemical formula , classed as a pnictogen hydride. Pure phosphine is odorless, but technical grade samples have a highly unpleasant odor like rotting ...
, 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 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 ...
. This initial example expanded into the concept of the
redox condensation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a de ...
reaction, in which a weak acid and weak base catalyze a condensation by means of a
redox
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...
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 R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyl ...
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 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 are ...
and
amides, 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 R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyl ...
in the presence of
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 ...
to yield an
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 ...
, creating what is now known as the
Mitsunobu reaction.
Modifications to the aldol reaction
The
aldol reaction
The aldol reaction is a means of forming carbon–carbon bonds in organic chemistry.
Discovered independently by the Russian chemist Alexander Borodin in 1869 and by the French chemist Charles-Adolphe Wurtz in 1872, the reaction combines two c ...
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 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. A compound containin ...
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
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 relocation of a hyd ...
ized into either an enol or enolate. However, when both carbonyls are similar in
pKa 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 a ...
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 charged, have an atom that ca ...
, 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 monovalent chemical groups (or two separate substitution sites in the same molecule). The name may also refer to the specific compound eth ...
with thioboronite produced a beta-hydroxyalkanethioate via a vinyloxyborane intermediate that would perform an aldol reaction with
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 ...
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 ( systematic name: trifluoromethanesulfonate), is a functional group with the formula and structure . The triflate group is often represented by , as opposed to −Tf, which is the triflyl group, . For example, ...
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
Titanium is a chemical element with the symbol Ti and atomic number 22. Found in nature only as an oxide, it can be reduced to produce a lustrous transition metal with a silver color, low density, and high strength, resistant to corrosion in s ...
. In 1973, he reported that titanium(IV) chloride treated with
zinc
Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc 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 t ...
powder catalyzed a
pinacol coupling of carbonyls in
THF which formed an
alkene
In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond.
Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
after reflux with
1,4-dioxane
1,4-Dioxane () is a heterocyclic organic compound, classified as an ether. It is a colorless liquid with a faint sweet odor similar to that of diethyl ether. The compound is often called simply dioxane because the other dioxane isomers ( 1,2 ...
. 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 sp ...
to activate aldehydes for reaction with
silyl enol ethers in what became known as the
Mukaiyama aldol reaction
The Mukaiyama aldol addition is an organic reaction and a type of aldol reaction between a silyl enol ether and an aldehyde or formate. The reaction was discovered by Teruaki Mukaiyama (1927–2018) in 1973. His choice of reactants allows for ...
. Published in 1973 as Mukaiyama was in the process of migrating to the
University of Tokyo
, abbreviated as or UTokyo, is a public research university located in Bunkyō, Tokyo, Japan. Established in 1877, the university was the first Imperial University and is currently a Top Type university of the Top Global University Project by ...
, 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 called Ciconiidae, and make up the order Ciconiiformes . Ciconiiformes previously included a number of other families, such as herons a ...
) 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 (''kheir''), "hand", a familiar chiral object.
An object or a system is ''chiral'' if it is distinguishable from i ...
ligands and induce
enantioselectivity. 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 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 R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyl ...
and an
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 ...
or similar functional groups to form an
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 ...
linkage. In the initial stage of the process, the carboxyl
displaces the
halogen 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 charged, have an atom that ca ...
and also serves as a good
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 ...
in a subsequent
nucleophilic acyl substitution 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 a ...
. 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 with the symbol Br and atomic number 35. It is the third-lightest element in group 17 of the periodic table (halogens) and is a volatile red-brown liquid at room temperature that evaporates readily to form a simil ...
as the halogen. In the years since its discovery, a number of different onium salts of
aza-
The prefix aza- is used in organic chemistry to form names of organic compounds where a carbon atom is replaced by a nitrogen atom. The related term "deaza-" refers to when a nitrogen is removed and, usually, a carbon atom is put in its place. ...
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 chemistry, aromaticity is a chemical property of cyclic (ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to sat ...
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 ...
anhydride 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 sp ...
catalyst.
Taxol synthesis
In the early 1990s, at least thirty separate groups were working on the total synthesis of the chemotherapy medicine
paclitaxel
Paclitaxel (PTX), sold under the brand name Taxol among others, is a chemotherapy medication used to treat a number of types of cancer. This includes ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical can ...
(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
, abbreviated as or UTokyo, is a public research university located in Bunkyō, Tokyo, Japan. Established in 1877, the university was the first Imperial University and is currently a Top Type university of the Top Global University Project by ...
after reaching the mandatory age of 60 and set up an academic lab at the
Tokyo University of Science
, formerly "Science University of Tokyo" or TUS, informally or simply is a private research university located in Shinjuku, Tokyo, Japan.
History
Tokyo University of Science was founded in 1881 as The Tokyo Academy of Physics by 21 graduat ...
. 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
Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
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, joining it with benzaldehyde with a
Mukaiyama aldol addition, and creating the amide from the alcohol via a
Mitsunobu reaction 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 ( 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 ...
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
Sulfenamides (also spelled sulphenamides) are a class of organosulfur compounds characterized by the general formula RSNR'2, where R and R' are H, alkyl, or aryl.Capozzi, G., Modena, G., Pasquato, L. in "Chemistry of Sulphenyl Halides and Sulfe ...
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 ( pl, Polska Akademia Nauk, 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 ...
in 1986
*
Person of Cultural Merit
is an official Japanese recognition and honor 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, established on February 11, 1937. The order has one class only, and may be awarded to men and women for contributions to Japan's art, literature, science, technology, or anything related to culture in general; recipient ...
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'', the ScienceDirect collection of electronic journals, '' Trends'', ...
in 1998
*
Sir Derek Barton Gold Medal from the
Royal Society of Chemistry
The Royal Society of Chemistry (RSC) is a learned society (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 Ro ...
in 1998
References
{{DEFAULTSORT:Mukaiyama, Teruaki
1927 births
2018 deaths
People from Nagano (city)
Tokyo Institute of Technology alumni
University of Tokyo alumni
Tokyo Institute of Technology faculty
Organic chemists
Japanese chemists
20th-century chemists
21st-century chemists