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The Mukaiyama aldol addition is an
A racemic mix of enantiomers is built. If Z- or E-enol silanes are used in this reaction a mixture of four products occurs, yielding two racemates.
Whether the ''anti''-
In the cited example the Lewis acid TiCl4 is used. First, the Lewis acid activates the aldehyde component followed by carbon-carbon bond formation between the enol silane and the activated aldehyde.
With the loss of a chlorosilane the compound 1 is built. The desired product, a racemate of 2 and 3, is obtained by aqueous work-up.
Ketone reactions of this type require higher reaction temperatures. For this work Mukaiyama was inspired by earlier work done by 
and a second one with an amine 
Utilization of chiral Lewis acid complexes and Lewis bases in asymmetric catalytic processes is the fastest-growing area in the usage of the Mukaiyama aldol reaction.
organic reaction
Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, Mechanistic Organ ...
and a type of 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 carb ...
between a silyl enol ether
Silyl enol ethers in organic chemistry are a class of organic compounds that share a common functional group composed of an enolate bonded through its oxygen end to an organosilicon group. They are important intermediates in organic synthesis.
Syn ...
and an 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 grou ...
or formate
Formate (IUPAC name: methanoate) is the conjugate base of formic acid. Formate is an anion () or its derivatives such as ester of formic acid. The salts and esters are generally colorless.Werner Reutemann and Heinz Kieczka "Formic Acid" in ''Ull ...
. The reaction was discovered by Teruaki Mukaiyama
was a Japanese organic chemist. One of the most prolific chemists of the 20th century in the field of organic synthesis, Mukaiyama helped establish the field of organic chemistry in Japan after World War II.
Education
Mukaiyama studied chemistr ...
(1927–2018) in 1973. His choice of reactants allows for a crossed aldol reaction between an aldehyde and a 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 bo ...
or a different aldehyde without self-condensation of the aldehyde. For this reason the reaction is used extensively in 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 ...
.
General reaction scheme
The Mukaiyama aldol addition is a Lewis acid mediated addition of enol silanes to carbonyl compounds. In this reaction compounds with various organic groups can be used (see educts). A basic version (R2 = H) without the presence of chiral catalysts is shown below.
A racemic mix of enantiomers is built. If Z- or E-enol silanes are used in this reaction a mixture of four products occurs, yielding two racemates.
Whether the ''anti''-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 ...
or the ''syn''-diastereomer is built depends largely on reaction conditions, substrates and Lewis acids.
The archetypical reaction is that of the silyl enol ether of cyclohexanone
Cyclohexanone is the organic compound with the formula (CH2)5CO. The molecule consists of six-carbon cyclic molecule with a ketone functional group. This colorless oily liquid has an odor reminiscent of acetone. Over time, samples of cyclohexan ...
with benzaldehyde
Benzaldehyde (C6H5CHO) is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful.
It is a colorless liquid with a characteristic almond-like odor. ...
. At room temperature
Colloquially, "room temperature" is a range of air temperatures that most people prefer for indoor settings. It feels comfortable to a person when they are wearing typical indoor clothing. Human comfort can extend beyond this range depending on ...
it produces a diastereomeric
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 di ...
mixture of threo
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 ...
(63%) and erythro
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 ...
(19%) β-hydroxyketone as well as 6% of the exocyclic
In organic chemistry, an alicyclic compound contains one or more all-carbon rings which may be either saturated or unsaturated, but do not have aromatic character. Alicyclic compounds may have one or more aliphatic side chains attached.
The s ...
enone condensation product. In its original scope the Lewis acid (titanium tetrachloride
Titanium tetrachloride is the inorganic compound with the formula . It is an important intermediate in the production of titanium metal and the pigment titanium dioxide. is a volatile liquid. Upon contact with humid air, it forms thick clouds o ...
) was used in stoichiometric amounts but truly catalytic systems exist as well. The reaction is also optimized for asymmetric synthesis
Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecul ...
.
Mechanism
Below, the reaction mechanism is shown with R2 = H:
In the cited example the Lewis acid TiCl4 is used. First, the Lewis acid activates the aldehyde component followed by carbon-carbon bond formation between the enol silane and the activated aldehyde.
With the loss of a chlorosilane the compound 1 is built. The desired product, a racemate of 2 and 3, is obtained by aqueous work-up.
Scope
A typical reaction involving two ketones is that betweenacetophenone
Acetophenone is the organic compound with the formula C6H5C(O)CH3. It is the simplest aromatic ketone. This colorless, viscous liquid is a precursor to useful resins and fragrances.
Production
Acetophenone is formed as a byproduct of the cumene p ...
as the enol and acetone
Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour.
Acetone is miscib ...
:
Ketone reactions of this type require higher reaction temperatures. For this work Mukaiyama was inspired by earlier work done by Georg Wittig
Georg Wittig (; 16 June 1897 – 26 August 1987) was a German chemist who reported a method for synthesis of alkenes from aldehydes and ketones using compounds called phosphonium ylides in the Wittig reaction. He shared the Nobel Prize in Che ...
in 1966 on crossed aldol reactions with lithiated 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 ...
s. Competing work with lithium enolate aldol reactions was published also in 1973 by Herbert O. House.
Mukaiyama employed in his rendition of taxol total synthesis
Paclitaxel total synthesis in organic chemistry is a major ongoing research effort in the total synthesis of paclitaxel (Taxol). This diterpenoid is an important drug in the treatment of cancer but, also expensive because the compound is harveste ...
(1999) two aldol additions,TBS = t-butyldimethylsilyl, Bn = benzyl, PMB = p-methoxybenzyl ether one with a ketene silyl acetal and excess magnesium bromide
Magnesium bromide is a chemical compound of magnesium and bromine, with the chemical formula . It is white and deliquescent crystalline solid. It is often used as a mild sedative and as an anticonvulsant for treatment of nervous disorders. It is ...
:
and a second one with an amine chiral ligand
Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecu ...
and a triflate salt catalyst:
Utilization of chiral Lewis acid complexes and Lewis bases in asymmetric catalytic processes is the fastest-growing area in the usage of the Mukaiyama aldol reaction.
References
{{reflist, 30em Addition reactions Name reactions