The Ojima lactam is an
organic compound
Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-co ...
of some importance in the commercial production of
Taxol
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 by ...
. This
lactam
A lactam is a Cyclic compound, cyclic amide, formally derived from an amino alkanoic acid through cyclization reactions. The term is a portmanteau of the words ''lactone'' + ''amide''.
Nomenclature
Greek_alphabet#Letters, Greek prefixes in alpha ...
was first synthesized by
Iwao Ojima.
The
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 ...
is an illustration of
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 ...
via a
chiral auxiliary
In stereochemistry, a chiral auxiliary is a Stereogenic center, stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxil ...
.
The reaction centers around an
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 bon ...
-
lithium
Lithium (from , , ) is a chemical element; it has chemical symbol, symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard temperature and pressure, standard conditions, it is the least dense metal and the ...
enolate
In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl () compounds. Rarely isolated, they are widely used as reagents in the Organic synthesis, synthesis of organic compounds.
Bonding and structure
Enolate ...
cycloaddition
In organic chemistry, a cycloaddition is a chemical reaction in which "two or more Unsaturated hydrocarbon, unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of th ...
. In order to ensure the correct
stereochemistry
Stereochemistry, a subdiscipline of chemistry, studies the spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereoisomers, which are defined ...
(the
phenyl
In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula , and is often represented by the symbol Ph (archaically φ) or Ø. The phenyl group is closely related to benzene and can be viewed as a benzene ...
group and the
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 ...
must adopt a
cis configuration CIS may refer to:
Computing
* Card information structure, formatting and organization data stored on a PC card
* Center for Internet Security, cybersecurity benchmarks, controls, practices and tools
* Center for Internet and Society (disambiguati ...
) in the
β-lactam a
chiral auxiliary
In stereochemistry, a chiral auxiliary is a Stereogenic center, stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxil ...
is used in the enolate synthesis. The enolate synthesis starts from
glycolic acid
Glycolic acid (or hydroxyacetic acid; chemical formula ) is a colorless, odorless and hygroscopic crystal, crystalline solid, highly solubility, soluble in water. It is used in various skin care, skin-care products. Glycolic acid is widespread in ...
. The
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 hydroxy ...
group is protected by a
benzyl
In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure . Benzyl features a benzene ring () attached to a methylene group ().
Nomenclature
In IUPAC nomenclature, the prefix benzyl refers to a substituent ...
group and the
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 ...
is activated by reaction with
thionyl chloride
Thionyl chloride is an inorganic compound with the chemical formula . It is a moderately Volatility (chemistry), volatile, colourless liquid with an unpleasant acrid odour. Thionyl chloride is primarily used as a Halogenation, chlorinating reagen ...
to the
acid chloride
In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group . Their formula is usually written , where R is a side chain. They are reactive derivatives of carboxylic acids (). A specific example o ...
. The acid chloride reacts with the
chiral auxiliary
In stereochemistry, a chiral auxiliary is a Stereogenic center, stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxil ...
trans-2-phenyl-1-cyclohexanol. The benzyl group is then removed and replaced by a TES
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 ...
by reaction with
triethylsilyl chloride. Reaction with
phenyllithium
Phenyllithium is an organometallic agent with the empirical formula . It is most commonly used as a metalating agent in organic syntheses and a substitute for Grignard reagents for introducing phenyl groups in organic syntheses. Crystalline phenyl ...
affords the
enolate
In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl () compounds. Rarely isolated, they are widely used as reagents in the Organic synthesis, synthesis of organic compounds.
Bonding and structure
Enolate ...
.
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 bon ...
synthesis is a reaction of
hexamethyldisilazane with phenyllithium to a strong amide base followed by a
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 ...
with
benzaldehyde
Benzaldehyde (C6H5CHO) is an organic compound consisting of a benzene ring with a formyl substituent. It is among the simplest aromatic aldehydes and one of the most industrially useful.
It is a colorless liquid with a characteristic almond-li ...
.
Both imine and enole intermediate join in a
cycloaddition
In organic chemistry, a cycloaddition is a chemical reaction in which "two or more Unsaturated hydrocarbon, unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of th ...
reaction followed by an
intramolecular substitution of the amine with expulsion of the chiral auxiliary to the
cis-
lactam
A lactam is a Cyclic compound, cyclic amide, formally derived from an amino alkanoic acid through cyclization reactions. The term is a portmanteau of the words ''lactone'' + ''amide''.
Nomenclature
Greek_alphabet#Letters, Greek prefixes in alpha ...
. The triethylsilyl group is removed by
hydrogen fluoride
Hydrogen fluoride (fluorane) is an Inorganic chemistry, inorganic compound with chemical formula . It is a very poisonous, colorless gas or liquid that dissolves in water to yield hydrofluoric acid. It is the principal industrial source of fluori ...
and the benzoyl group is added in a
Schotten-Baumann reaction.
References
{{Reflist
Lactams