The Nazarov cyclization reaction (often referred to as simply the Nazarov cyclization) is a
chemical reaction
A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...
used in
organic chemistry
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.; ...
for the synthesis of
cyclopentenone
2-Cyclopentenone is a ketone with chemical formula and CAS number 930-30-3. It is structurally similar to cyclopentanone, with the additional feature of α-β unsaturation in the ring system. 2-Cyclopentenone contains two functional groups, a k ...
s. The reaction is typically divided into ''classical'' and ''modern'' variants, depending on the
reagent
In chemistry, a reagent ( ) or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms ''reactant'' and ''reagent'' are often used interchangeably, but reactant specifies a ...
s and
substrates employed. It was originally discovered by
Ivan Nikolaevich Nazarov (1906–1957) in 1941 while studying the rearrangements of allyl vinyl ketones.
![Nazarov cyclization](https://upload.wikimedia.org/wikipedia/commons/2/29/Nazarov_cyclization.png)
As originally described, the Nazarov cyclization involves the activation of a
divinyl ketone using a
stoichiometric
Stoichiometry refers to the relationship between the quantities of reactants and products before, during, and following chemical reactions.
Stoichiometry is founded on the law of conservation of mass where the total mass of the reactants equal ...
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 ...
or
protic acid
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 sequ ...
promoter. The key step of the reaction mechanism involves a
cationic
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
4π-
electrocyclic ring closure which forms the cyclopentenone product (See
Mechanism
Mechanism may refer to:
*Mechanism (engineering), rigid bodies connected by joints in order to accomplish a desired force and/or motion transmission
*Mechanism (biology), explaining how a feature is created
*Mechanism (philosophy), a theory that a ...
below). As the reaction has been developed, variants involving substrates other than divinyl ketones and promoters other than Lewis acids have been subsumed under the name Nazarov cyclization provided that they follow a similar
mechanistic pathway.
The success of the Nazarov cyclization as a tool in organic synthesis stems from the utility and ubiquity of
cyclopentenone
2-Cyclopentenone is a ketone with chemical formula and CAS number 930-30-3. It is structurally similar to cyclopentanone, with the additional feature of α-β unsaturation in the ring system. 2-Cyclopentenone contains two functional groups, a k ...
s as both motifs in
natural product
A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...
s (including
jasmone
Jasmone is an organic compound, which is a volatile portion of the oil from jasmine flowers. It is a colorless to pale yellow liquid. Jasmone can exist in two isomeric forms with differing geometry around the pentenyl double bond, ''cis''-jasmon ...
, the
aflatoxin
Aflatoxins are various poisonous carcinogens and mutagens that are produced by certain molds, particularly ''Aspergillus'' species. The fungi grow in soil, decaying vegetation and various staple foodstuffs and commodities such as hay, sweetcorn ...
s, and a subclass of
prostaglandin
The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...
s) and as useful synthetic intermediates for
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 ...
. The reaction has been used in several total syntheses and several reviews have been published.
Mechanism
The mechanism of the classical Nazarov cyclization reaction was first demonstrated experimentally by
Shoppee to be an
intramolecular electrocyclization In organic chemistry, an electrocyclic reaction is a type of pericyclic rearrangement where the net result is one pi bond being converted into one sigma bond or vice versa. These reactions are usually categorized by the following criteria:
* React ...
and is outlined below. Activation of 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 bo ...
by the acid catalyst generates a
pentadienyl
In organic chemistry, pentadienyl refers to the organic radical, anion, or cation with the formula , where ''z'' = 0, −1, +1, respectively.
Organometallic chemistry
In organometallic chemistry, the pentadienyl anion is a ligand, the acyclic ana ...
cation, which undergoes a thermally allowed 4π
conrotatory
An electrocyclic reaction can either be classified as conrotatory or disrotatory based on the rotation at each end of the molecule. In conrotatory mode, both atomic orbitals of the end groups turn in the same direction (such as both atomic orbital ...
electrocyclization as dictated by the
Woodward-Hoffman rules. This generates an oxyallyl cation which undergoes an
elimination reaction
An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one- or two-step mechanism. The one-step mechanism is known as the E2 reaction, and the two-step mechanism is known as the E1 ...
to lose a β-hydrogen. Subsequent
tautomerization
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 hydr ...
of 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 synthesis of organic compounds.
Bonding and structure
Enolate anions are electr ...
produces the cyclopentenone product.
![Nazarov reaction mechanism](https://upload.wikimedia.org/wikipedia/commons/4/40/Nazarov_reaction_mechanism.png)
As noted above, variants that deviate from this template are known; what designates a Nazarov cyclization in particular is the generation of the pentadienyl
cation
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
followed by electrocyclic ring closure to an oxyallyl cation. In order to achieve this transformation, the molecule must be in the s-trans/s-trans
conformation, placing the
vinyl
Vinyl may refer to:
Chemistry
* Polyvinyl chloride (PVC), a particular vinyl polymer
* Vinyl cation, a type of carbocation
* Vinyl group, a broad class of organic molecules in chemistry
* Vinyl polymer, a group of polymers derived from vinyl m ...
groups in an appropriate orientation. The propensity of the system to enter this conformation dramatically influences
reaction rate
The reaction rate or rate of reaction is the speed at which a chemical reaction takes place, defined as proportional to the increase in the concentration of a product per unit time and to the decrease in the concentration of a reactant per unit ...
, with α-substituted substrates having an increased population of the requisite
conformer
Conformer is a clear acrylic shell fitted after an enucleation if the final artificial eye is not available at the time of surgery to hold the shape of the eye socket and allow the eyelids to blink over the shell without rubbing the suture line. ...
due to
allylic strain
250 px , right , Allylic strain in an olefin.
Allylic strain (also known as A1,3 strain, 1,3-allylic strain, or A-strain) in organic chemistry is a type of strain energy resulting from the interaction between a substituent on one end of an olef ...
. Coordination of an electron donating α-substituent by the catalyst can likewise increase the reaction rate by enforcing this conformation.
![Nazarov conformation](https://upload.wikimedia.org/wikipedia/commons/4/43/Nazarov_conformation.png)
Similarly, β-substitution directed inward restricts the s-trans conformation so severely that
E-Z 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 tautomeriz ...
has been shown to occur in advance of cyclization on a wide range of substrates, yielding the trans cyclopentenone regardless of initial configuration. In this way, the Nazarov cyclization is a rare example of a
stereoselective
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 of ...
pericyclic reaction
In organic chemistry, a pericyclic reaction is the type of organic reaction wherein the transition state of the molecule has a cyclic geometry, the reaction progresses in a concerted fashion, and the bond orbitals involved in the reaction overlap ...
, whereas most
electrocyclization In organic chemistry, an electrocyclic reaction is a type of pericyclic rearrangement where the net result is one pi bond being converted into one sigma bond or vice versa. These reactions are usually categorized by the following criteria:
* React ...
s are
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 ...
. The example below uses
triethylsilyl hydride to trap the oxyallyl cation so that no elimination occurs.
(See
Interrupted cyclizations below)
![Nazarovselective](https://upload.wikimedia.org/wikipedia/commons/6/69/Nazarovselective.png)
Along this same vein, allenyl vinyl ketones of the type studied extensively by Marcus Tius of the
University of Hawaii
A university () is an institution of higher (or tertiary) education and research which awards academic degrees in several academic disciplines. Universities typically offer both undergraduate and postgraduate programs. In the United States, th ...
show dramatic rate acceleration due to the removal of β-hydrogens, obviating a large amount of steric strain in the s-cis conformer.
Classical Nazarov cyclizations
Though cyclizations following the general template above had been observed prior to Nazarov's involvement, it was his study of the rearrangements of allyl vinyl
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 ...
s that marked the first major examination of this process. Nazarov correctly reasoned that the
allylic
In organic chemistry, an allyl group is a substituent with the structural formula , where R is the rest of the molecule. It consists of a methylene bridge () attached to a vinyl group (). The name is derived from the scientific name for garlic, . ...
olefin
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 ...
isomerized ''
in situ
''In situ'' (; often not italicized in English) is a Latin phrase that translates literally to "on site" or "in position." It can mean "locally", "on site", "on the premises", or "in place" to describe where an event takes place and is used in ...
'' to form a divinyl ketone before ring closure to the cyclopentenone product. The reaction shown below involves an
alkyne
\ce
\ce
Acetylene
\ce
\ce
\ce
Propyne
\ce
\ce
\ce
\ce
1-Butyne
In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and n ...
oxymercuration reaction
The oxymercuration reaction is an electrophilic addition organic reaction that transforms an alkene into a neutral alcohol. In oxymercuration, the alkene reacts with mercuric acetate (AcO–Hg–OAc) in aqueous solution to yield the addition of ...
to generate the requisite ketone.
![NazarovOriginal](https://upload.wikimedia.org/wikipedia/commons/d/d7/NazarovOriginal.png)
Research involving the reaction was relatively quiet in subsequent years, until in the mid-1980s when several syntheses employing the Nazarov cyclization were published. Shown below are key steps in the syntheses of Trichodiene and Nor-Sterepolide, the latter of which is thought to proceed via an unusual
alkyne
\ce
\ce
Acetylene
\ce
\ce
\ce
Propyne
\ce
\ce
\ce
\ce
1-Butyne
In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and n ...
-
allene
In organic chemistry, allenes are organic compounds in which one carbon atom has double bonds with each of its two adjacent carbon centres (). Allenes are classified as diene#Classes, cumulated dienes. The parent compound of this class is propa ...
isomerization that generates the divinyl ketone.
Shortcomings
The classical version of the Nazarov cyclization suffers from several drawbacks which modern variants attempt to circumvent. The first two are not evident from the mechanism alone, but are indicative of the barriers to cyclization; the last three stem from selectivity issues relating to elimination and protonation of the intermediate.
# Strong Lewis or protic acids are typically required for the reaction (e.g.
TiCl4,
BF3,
MeSO3H). These promoters are not compatible with sensitive functional groups, limiting the substrate scope.
# Despite the mechanistic possibility for
catalysis
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
, multiple
equivalent
Equivalence or Equivalent may refer to:
Arts and entertainment
*Album-equivalent unit, a measurement unit in the music industry
*Equivalence class (music)
*''Equivalent VIII'', or ''The Bricks'', a minimalist sculpture by Carl Andre
*''Equivale ...
s of the promoter are often required in order to effect the reaction. This limits the
atom economy
Atom economy (atom efficiency/percentage) is the conversion efficiency of a chemical process in terms of all atoms involved and the desired products produced. The simplest definition was introduced by Barry Trost in 1991 and is equal to the ratio ...
of the reaction.
# The elimination step is not
regioselective
In chemistry, regioselectivity is the preference of chemical bonding or breaking in one direction over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base ...
; if multiple β-hydrogens are available for elimination, various products are often observed as mixtures. This is highly undesirable from an efficiency standpoint as arduous
separation is typically required.
# Elimination destroys a potential
stereocenter
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 ...
, decreasing the potential usefulness of the reaction.
# Protonation of the enolate is sometimes not
stereoselective
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 of ...
, meaning that products can be formed as mixtures 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.
Modern variants
The shortcomings noted above limit the usefulness of the Nazarov cyclization reaction in its canonical form. However, modifications to the reaction focused on remedying its issues continue to be an active area of
academic research
Research is " creative and systematic work undertaken to increase the stock of knowledge". It involves the collection, organization and analysis of evidence to increase understanding of a topic, characterized by a particular attentiveness ...
. In particular, the research has focused on a few key areas: rendering the reaction
catalytic
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
in the promoter, effecting the reaction with more mild promoters to improve
functional group
In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...
tolerance, directing the
regioselectivity
In chemistry, regioselectivity is the preference of chemical bonding or breaking in one direction over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base ...
of the elimination step, and improving the overall
stereoselectivity
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 of ...
. These have been successful to varying degrees.
Additionally, modifications focused on altering the progress of the reaction, either by generating the pentadienyl cation in an unorthodox fashion or by having the oxyallyl cation "intercepted" in various ways. Furthermore,
enantioselective
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...
variants of various kinds have been developed. The sheer volume of literature on the subject prevents a comprehensive examination of this field; key examples are given below.
Silicon-directed cyclization
The earliest efforts to improve the selectivity of the Nazarov cyclization took advantage of the
β-silicon effect in order to direct the regioselectivity of the elimination step. This chemistry was developed most extensively by Professor Scott Denmark of the
University of Illinois, Urbana-Champaign
The University of Illinois Urbana-Champaign (U of I, Illinois, University of Illinois, or UIUC) is a public land-grant research university in Illinois in the twin cities of Champaign and Urbana. It is the flagship institution of the Universi ...
in the mid-1980s and utilizes stoichiometric amounts of
iron trichloride
Iron(III) chloride is the inorganic compound with the formula . Also called ferric chloride, it is a common compound of iron in the +3 oxidation state. The anhydrous compound is a crystalline solid with a melting point of 307.6 °C. The colo ...
to promote the reaction. With
bicyclic
In chemistry, a bicyclic molecule () is a molecule that features two joined rings. Bicyclic structures occur widely, for example in many biologically important molecules like α-thujene and camphor. A bicyclic compound can be carbocyclic (all o ...
products, the
cis
Cis or cis- may refer to:
Places
* Cis, Trentino, in Italy
* In Poland:
** Cis, Świętokrzyskie Voivodeship, south-central
** Cis, Warmian-Masurian Voivodeship, north
Math, science and biology
* cis (mathematics) (cis(''θ'')), a trigonome ...
isomer was selected for to varying degrees.
![Siliconnazarov](https://upload.wikimedia.org/wikipedia/commons/b/bb/Siliconnazarov.png)
The silicon-directed Nazarov cyclization reaction was subsequently employed in the synthesis of the natural product Silphinene, shown below. The cyclization takes place before elimination of the
benzyl alcohol
Benzyl alcohol is an aromatic alcohol with the formula C6H5CH2OH. The benzyl group is often abbreviated "Bn" (not to be confused with "Bz" which is used for benzoyl), thus benzyl alcohol is denoted as BnOH. Benzyl alcohol is a colorless liquid w ...
moiety, so that the resulting
stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...
of the newly formed ring arises from approach of the silyl alkene ''anti'' to the ether.
Polarization
Drawing on the substituent effects compiled over various trials of the reaction, Professor Alison Frontier of the
University of Rochester
The University of Rochester (U of R, UR, or U of Rochester) is a private research university in Rochester, New York. The university grants undergraduate and graduate degrees, including doctoral and professional degrees.
The University of Roc ...
developed a paradigm for "polarized" Nazarov cyclizations in which
electron donating
An electronic effect influences the structure, reactivity, or properties of molecule but is neither a traditional bond nor a steric effect. In organic chemistry, the term stereoelectronic effect is also used to emphasize the relation between th ...
and
electron withdrawing group
In chemistry, an electron-withdrawing group (EWG) is a substituent that has some of the following kinetic and thermodynamic implications:
*with regards to electron transfer, electron-withdrawing groups enhance the oxidizing power tendency of ...
s are used to improve the overall selectivity of the reaction. Creation of an effective
vinyl
Vinyl may refer to:
Chemistry
* Polyvinyl chloride (PVC), a particular vinyl polymer
* Vinyl cation, a type of carbocation
* Vinyl group, a broad class of organic molecules in chemistry
* Vinyl polymer, a group of polymers derived from vinyl m ...
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 ...
and vinyl
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 carries ...
in the substrate allows catalytic activation with
copper triflate
Copper(II) triflate is the copper(II) salt of trifluoromethanesulfonic acid
Triflic acid, the short name for trifluoromethanesulfonic acid, TFMS, TFSA, HOTf or TfOH, is a sulfonic acid with the chemical formula CF3SO3H. It is one of the stronge ...
and regioselective elimination. In addition, the electron withdrawing group increases the acidity of the α-proton, allowing selective formation of the trans-α-epimer via equilibration.
![Polarized Nazarov](https://upload.wikimedia.org/wikipedia/commons/d/d6/Polarized_Nazarov.png)
It is often possible to achieve catalytic activation using a donating or withdrawing group alone, although the efficiency of the reaction (yield, reaction time, etc.) is typically lower.
Alternative cation generation
By extension, any pentadienyl cation regardless of its origin is capable of undergoing a Nazarov cyclization. There have been a large number of examples published where the requisite cation is arrived at by a variety of rearrangements.
One such example involves the silver catalyzed cationic ring opening of allylic dichloro cylopropanes. The silver salt facilitates loss of chloride via precipitation of insoluble
silver chloride
Silver chloride is a chemical compound with the chemical formula Ag Cl. This white crystalline solid is well known for its low solubility in water (this behavior being reminiscent of the chlorides of Tl+ and Pb2+). Upon illumination or heating, ...
.
![Westchloro](https://upload.wikimedia.org/wikipedia/commons/c/ce/Westchloro.png)
In the
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 ...
of rocaglamide,
epoxidation
In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...
of a vinyl alkoxyallenyl
stannane
Stannane or tin hydride is an inorganic compound with the chemical formula . It is a colourless gas and the tin analogue of methane. Stannane can be prepared by the reaction of and .
:
Stannane decomposes slowly at room temperature to give ...
likewise generates a pentadienyl cation via ring opening of the resultant
epoxide
In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...
.
Interrupted cyclization
Once the cyclization has occurred, an oxyallyl cation is formed. As discussed extensively above, the typical course for this intermediate is
elimination followed by
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 synthesis of organic compounds.
Bonding and structure
Enolate anions are electr ...
tautomerization
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 hydr ...
. However, these two steps can be interrupted by various
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 ...
s and
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 carries ...
s, respectively. Oxyallyl cation trapping has been developed extensively by Fredrick G. West of the
University of Alberta
The University of Alberta, also known as U of A or UAlberta, is a public research university located in Edmonton, Alberta, Canada. It was founded in 1908 by Alexander Cameron Rutherford,"A Gentleman of Strathcona – Alexander Cameron Rutherfor ...
and his review covers the field.
The oxyallyl cation can be trapped with
heteroatom
In chemistry, a heteroatom () is, strictly, any atom that is not carbon or hydrogen.
Organic chemistry
In practice, the term is usually used more specifically to indicate that non-carbon atoms have replaced carbon in the backbone of the molecula ...
and carbon
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 ...
s and can also undergo cationic
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 ...
s with various tethered partners. Shown below is a cascade reaction in which successive cation trapping generates a pentacyclic core in one step with complete
diastereoselectivity
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 ...
.
![Westcascade](https://upload.wikimedia.org/wikipedia/commons/7/7b/Westcascade.png)
Enolate trapping with various
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 carries ...
s is decidedly less common. In one study, the Nazarov cyclization is paired with a
Michael reaction
In organic chemistry, the Michael reaction or Michael addition is a reaction between a Michael donor (an enolate or other nucleophile) and a Michael acceptor (usually an α,β-unsaturated carbonyl) to produce a Michael adduct by creating a carbon ...
using an iridium catalyst to initiate
nucleophilic conjugate addition
Nucleophilic conjugate addition is a type of organic reaction. Ordinary nucleophilic additions or 1,2-nucleophilic additions deal mostly with additions to carbonyl compounds. Simple alkene compounds do not show 1,2 reactivity due to lack of polarit ...
of the enolate to
β-nitrostyrene. In this
tandem reaction
A cascade reaction, also known as a domino reaction or tandem reaction, is a chemical process that comprises at least two consecutive reactions such that each subsequent reaction occurs only in virtue of the chemical functionality formed in the p ...
the
iridium
Iridium is a chemical element with the symbol Ir and atomic number 77. A very hard, brittle, silvery-white transition metal of the platinum group, it is considered the second-densest naturally occurring metal (after osmium) with a density of ...
catalyst
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
is required for both conversions: it acts as the
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 ...
in the Nazarov cyclization and in the next step the
nitro
Nitro may refer to:
Chemistry
*Nitrogen, a chemical element and a gas except at very low temperatures, with which many compounds are formed:
**Nitro compound, an organic compound containing one or more nitro functional groups, -NO2
**Nitroalkene, ...
group of nitrostyrene first coordinates to iridium in a
ligand exchange
In coordination chemistry, a ligand is an ion or molecule (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 electr ...
with the carbonyl ester oxygen atom before the actual Michael addition takes place to the opposite face of the R-group.
Enantioselective variants
The development of an
enantioselective
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...
Nazarov cyclization is a desirable addition to the repertoire of Nazarov cyclization reactions. To that end, several variations have been developed utilizing
chiral auxiliaries
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 ...
and
chiral catalyst
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 ...
s.
Diastereoselective
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 ...
cyclizations are also known, in which extant
stereocenter
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 ...
s direct the cyclization. Almost all of the attempts are based on the idea of
torquoselectivity Torquoselectivity is a special kind of stereoselectivity observed in electrocyclic reactions in organic chemistry, defined as "the preference for inward or outward rotation of substituents in conrotatory
or disrotatory electrocyclic reactions." Torq ...
; selecting one direction for the vinyl groups to "rotate" in turn sets the stereochemistry as shown below.
![Torquoselectivity](https://upload.wikimedia.org/wikipedia/commons/3/3e/Torquoselectivity.png)
Silicon-directed Nazarov cyclizations can exhibit induced diastereoselectivity in this way. In the example below, the silyl-group acts to direct the cyclization by preventing the distant alkene from rotating "towards" it via unfavorable
steric interaction. In this way the silicon acts as a traceless
auxiliary
Auxiliary may refer to:
* A backup site or system
In language
* Auxiliary language (disambiguation)
* Auxiliary verb
In military and law enforcement
* Auxiliary police
* Auxiliaries, civilians or quasi-military personnel who provide support of ...
. (The starting material is not enantiopure but the retention of
enantiomeric excess
In stereochemistry, enantiomeric excess (ee) is a measurement of purity used for chiral substances. It reflects the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an ee of 0%, while a sin ...
suggests that the auxiliary directs the cyclization.)
![NazarovSiliconauxilliary](https://upload.wikimedia.org/wikipedia/commons/3/36/NazarovSiliconauxilliary.png)
Tius's allenyl substrates can exhibit axial to tetrahedral chirality transfer if enantiopure allenes are used. The example below generates a chiral diosphenpol in 64% yield and 95%
enantiomeric excess
In stereochemistry, enantiomeric excess (ee) is a measurement of purity used for chiral substances. It reflects the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an ee of 0%, while a sin ...
.
![Axialtotetrahedral transfer](https://upload.wikimedia.org/wikipedia/commons/7/7c/Axialtotetrahedral_transfer.png)
Tius has additionally developed a
camphor
Camphor () is a waxy, colorless solid with a strong aroma. It is classified as a terpenoid and a cyclic ketone. It is found in the wood of the camphor laurel ('' Cinnamomum camphora''), a large evergreen tree found in East Asia; and in the k ...
-based auxiliary for achiral allenes that was employed in the first asymmetric synthesis of
roseophilin
Roseophilin is an antibiotic isolated from '' Streptomyces griseoviridis'' shown to have antitumor activity. The chemical structure can be considered in terms of two components, a macrotricyclic segment and a heterocyclic side-chain. Several la ...
. The key step employs an unusual mixture of
hexafluoro-2-propanol
Hexafluoroisopropanol, commonly abbreviated HFIP, is the organic compound with the formula (CF3)2CHOH. This fluoroalcohol finds use as solvent and synthetic intermediate. It appears as a colorless, volatile liquid that is characterized by a stro ...
and
trifluoroethanol
2,2,2-Trifluoroethanol is the organic compound with the formula CF3CH2OH. Also known as TFE or trifluoroethyl alcohol, this colourless, water-miscible liquid has a smell reminiscent of ethanol. Due to the electronegativity of the trifluoromethyl ...
as solvent.
![Tiusroseophilin](https://upload.wikimedia.org/wikipedia/commons/9/90/Tiusroseophilin.png)
The first chiral Lewis acid promoted asymmetric Nazarov cyclization was reported by
Varinder Aggarwal
Varinder Kumar Aggarwal (born 1961) is a British organic chemist specialising in asymmetric synthesis. He is a Professor of Synthetic Chemistry at the School of Chemistry of the University of Bristol.
Early life
Aggarwal was born in 1961 in ...
and utilized copper (II)
bisoxazoline ligand In chemistry, bis(oxazoline) ligands (often abbreviated BOX ligands) are a class of privileged chiral ligands containing two oxazoline rings. They are typically C2‑symmetric and exist in a wide variety of forms; with structures based around CH ...
complexes with up to 98% ee. The enantiomeric excess was unaffected by use of 50 mol% of the copper complex but the yield was significantly decreased.
Related Reactions
Extensions of the Nazarov cyclization are generally also subsumed under the same name. For example, an α-β, γ-δ unsaturated
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 ...
can undergo a similar cationic conrotatory cyclization that is typically referred to as an iso-Nazarov cyclization reaction.
Other such extensions have been given similar names, including
homo
''Homo'' () is the genus that emerged in the (otherwise extinct) genus ''Australopithecus'' that encompasses the extant species ''Homo sapiens'' ( modern humans), plus several extinct species classified as either ancestral to or closely relate ...
-Nazarov cyclizations and
vinylogous
In organic chemistry, vinylogy is the transmission of electronic effects through a conjugated organic bonding system. The concept was introduced in 1926 by Ludwig Claisen to explain the acidic properties of formylacetone and related ketoaldehyde ...
Nazarov cyclizations.
Retro-Nazarov reaction
Because they overstabilize the pentadienyl cation, β-electron donating substituents often severely impede Nazarov cyclization. Building from this, several electrocyclic ring openings of β-alkoxy cyclopentanes have been reported. These are typically referred to as retro-Nazarov cyclization reactions.
Imino-Nazarov reaction
Nitrogen analogues of the Nazarov cyclization reaction (known as imino-Nazarov cyclization reactions) have few instances; there is one example of a generalized imino-Nazarov cyclization reported (shown below),
and several iso-imino-Nazarov reactions in the literature.
Even these tend to suffer from poor stereoselectivity, poor yields, or narrow scope. The difficulty stems from the relative over-stabilization of the pentadienyl cation by electron donation, impeding cyclization.
See also
*
Pauson–Khand reaction
The Pauson–Khand reaction (or PKR or PK-type reaction) is a chemical reaction described as a 2+2+1.html" ;"title="/nowiki>2+2+1">/nowiki>2+2+1/nowiki> cycloaddition between an alkyne, an alkene and carbon monoxide to form a α,β-cyclopentenone. ...
*
Electrocyclization In organic chemistry, an electrocyclic reaction is a type of pericyclic rearrangement where the net result is one pi bond being converted into one sigma bond or vice versa. These reactions are usually categorized by the following criteria:
* React ...
*
Cyclopentenone
2-Cyclopentenone is a ketone with chemical formula and CAS number 930-30-3. It is structurally similar to cyclopentanone, with the additional feature of α-β unsaturation in the ring system. 2-Cyclopentenone contains two functional groups, a k ...
*
Merrilactone A
References
{{Reflist, 2
Rearrangement reactions
Name reactions