Inverse electron demand Diels-Alder reaction
Encyclopedia
The Inverse electron demand Diels-Alder reaction, or DAINV is an organic chemical reaction, related to the Diels-Alder reaction
. Unlike the Diels-Alder (or DA) reaction, the DAINV is a cycloaddition
between an electron-rich dienophile and an electron-poor diene
. During a DAINV reaction, three pi-bonds are broken, and two sigma-bonds and one new pi-bond are formed. A prototypical DAINV reaction is shown on the right.
DAINV reactions often involve heteroatoms, and can be used to form heterocyclic compounds. This makes the DAINV reaction particularly useful in natural product syntheses, where the target compounds often contain heterocycles. Recently, the DAINV reaction has been used to synthesize a drug transport system for treatment of prostate cancer
cells.
and Kurt Alder
; they were awarded the Nobel Prize
in chemistry for their work in 1950. Since that time, use of the Diels-Alder reaction has become widespread. Conversely, DAINV does not have a clear date of inception, and lacks the comparative notoriety of the standard Diels-Alder. Much of the work in this area is attributed to Dale Boger, though other authors have published numerous papers on the subject.
The mechanism of the DAINV reaction is controversial. While it is accepted as a formal [4+2] cycloaddition
, it is not well understood whether or not the reaction is truly concerted. The accepted view is that most DAINV reactions occur via an asynchronous mechanism. The reaction proceeds via a single transition state, but not all bonds are formed or broken at the same time, as would be the case in a concerted mechanism.
The formal DAINV mechanism for the reaction of acrolein
and methyl vinyl ether
is shown in the figure to the right. Though not entirely accurate, it provides a useful model for the reaction. During the course of the reaction, three pi-bonds (labeled with red) are broken, and three new bonds are formed (labeled in blue): two sigma-bonds and one new pi-bond.
Transition State
Like the standard DA, DAINV reactions proceed via a single boat transition state
, despite not being concerted. The single boat transition state is a simplification, but DFT
calculations suggest that the time difference in bond scission and formation is minimal, and that despite potential asynchronicity, the reaction is concerted, with relevant bonds being either partially broken or partially formed at some point during the reaction. The near synchronicity of the DAINV means it can be treated similarly to the standard Diels-Alder reaction.
The reaction can be modeled using a closed, boat-like transition state, with all bonds being in the process of forming or breaking at some given point, and therefore must obey the Woodward-Hoffman general selection rules. This means that for a three component, six electron system, all components must interact in a suprafacial manner (or one suprafacial and two antarfacial). With all components being suprafacial, the allowed transition state
is boat-like; a chair-like transition state would result in three two-electron antarafacial components. The chair-like case is thermally disallowed by the Woodward-Hoffman rules.
In the standard Diels-Alder reaction, there are two components: the diene
, which is electron rich, and the dienophile, which is electron poor. The relative electron-richness and electron deficiency of the reactants can best be described visually, in a Molecular Orbital Diagram. In the standard Diels-Alder, the electron rich diene
has molecular orbitals that are higher in energy than the orbitals of the electron poor dienophile. This difference in relative orbital energies means that, of the frontier molecular orbitals
the HOMO
of the diene (HOMOdiene) and the LUMO
of the dienophile (LUMOdienophile) are more similar in energy than the HOMOdienophile and the LUMOdiene. The strongest orbital interaction is between the most similar frontier molecular orbitals: HOMOdiene and LUMOdienophile.
[4+2] Dimerization Reactions
Dimerization reactions are neither normally or inversely accelerated, and are usually low yielding. In this case, two monomers react in a DA fashion. Because the orbital energies are identical, there is no preference for interaction of the HOMO or the LUMO of either the diene or dienophile. The low yield of dimerization reactions is explained my second-order perturbation theory
. The LUMO and HOMO of each species are farther apart in energy in a dimerization than in either normally or inversely accelerated Diels-Alder. This means that the orbitals interact less, and there is a lower thermodynamic drive for dimerization.
Diels-Alder with inverse electron demand
In the dimerization reactions, the diene and dienophile were equally electron rich (or equally electron poor). If the diene becomes any less electron rich, the the dienophile any more so, the possbile [4+2] cycloaddition reaction will then be a DAINV reaction. In the DAINV reaction, the LUMOdiene and HOMOdienophile are closer in energy than the HOMOdiene and LUMOdienophile. Thus, the LUMOdiene and HOMOdienophile are the frontier orbitals that interact the most strongly, and result in the most energetically favourable bond formation.
Regiochemistry in DAINV reactions can be reliably predicted in many cases. This can be done one of two ways, either by electrostatic (charge) control, or orbital control.
Alder-Stein Principle
The Alder-Stein principle states that the stereochemistry of the reactants is maintained in the stereochemistry of the products during a Diels-Alder reaction. This means that groups which were cis in relation to one another in the starting materials will be syn to one another in the product, and groups that were trans to one another in the starting material will be anti in the product.
It is important to note that the Alder-Stein principle has no bearing on the relative orientation of groups on the two starting materials. One cannot predict, via this principle, whether a substituent on the diene will be syn or anti to a substituent on the dienophile. The Alder-Stein principle is only consistent across the self-same starting materials. The relationship is only valid for the groups on the diene alone, or the groups on the dienophile, alone. The relative orientation of groups between the two reactants can be predicted by the endo selection rule.
Endo selection rule
Similarly to the standard Diels-Alder reaction, the DAINV also obeys a general endo selection rule. In the standard Diels-Alder, it is known that electron withdrawing groups on the dienophile will approach endo, with respect to the diene. The exact cause of this selectivity is still debated, but the most accepted view is that endo approach maximizes secondary orbital overlap. The DAINV favors an endo orientation of electron donating substituents on the dienophile.Since all Diels-Alder reactions proceed through a boat transition state
, there is an "inside" and an "outside" of the transition state (inside and outside the "boat"). The substituents on the dienophile are considered "endo" if they are 'inside' the boat, and "exo" if they are on the outside.
The exo pathway would be favored by sterics, so a different explanation is needed to justify the general predominance of endo products. FMO theory can be used to explain this outcome. When the substituents of the dienophile are exo, there is no interaction between those substituents and the diene. However, when the dienophile substituents are endo, there is considerable orbital overlap with the diene. In the case of DAINV the overlap of the orbitals of the electron withdrawing substituents with the orbitals of the diene create a favorable bonding interaction, stabilizing the transition state. The energy of the transition state of a reaction is directly related to the activation energy
. Referring to the Arrhenius equation
, the reaction with the lower activation energy will proceed at a greater rate.
used in Inverse electron demand Diels-Alder are relatively electron-deficient species; compared to the standard Diels-Alder, where the diene is electron rich. These electron-poor species have lower molecular orbital
energies than their standard DA counterparts. This lowered energy results from the inclusion of either: A) electron withdrawing groups, or B) electronegative heteroatoms. Aromatic compounds can also react in DAINV reactions, such as triazines and tetrazines. Other common classes of dienes are oxo
- and aza
- butadienes.
The key quality of a good DAINV diene is a significantly lowered HOMO and LUMO, as compared to standard DA dienes. Below is a table showing a few commonly used DAINV dienes, their HOMO and LUMO energies, and some standard DA dienes, along with their respective MO energies.
The most important consideration in choice of dienophile is its relative orbital energies. Both HOMO and LUMO impact the rate and selectivity of the reaction. A table of common DAINV dienophiles, standard DA dienophiles, and their respective MO energies can be seen below.
A second table shows how electron richness in the dienophiles affects the rate of reaction with a very electron poor diene, namely hexachlorocyclopentadiene
.
DAINV reactions have been utilized for the synthesis of several natural products, including (-)-CC-1065, a parent compound in the Duocarmycin
series, which found use as an anticancer treatment. Several drug candidates in this series have progress into clinical trials. The DAINV reaction was used to synthesise the PDE-I and PDE-II sections of (-)-CC-1065. The first reaction in the sequence is a DAINV reaction between the tetrazine
and vinyl acetal, followed by a retro Diels-Alder to afford a 1,2-diazine
product. After several more steps, an intramolecular
DA,sub>INV reaction occurs, followed again by a retro Diels-Alder in situ, to afford an indoline
product. This indoline is a converted into either PDE-I or PDE-II in a few synthetic steps.
Diels-Alder reaction
The Diels–Alder reaction is an organic chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. The reaction can proceed even if some of the atoms in the newly formed ring are not carbon...
. Unlike the Diels-Alder (or DA) reaction, the DAINV is a cycloaddition
Cycloaddition
A cycloaddition is a pericyclic chemical reaction, in which "two or more unsaturated molecules combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity." The resulting reaction is a cyclization reaction.Cycloadditions are usually described by the...
between an electron-rich dienophile and an electron-poor diene
Diene
In organic chemistry a diene or diolefin is a hydrocarbon that contains two carbon double bonds.Conjugated dienes are functional groups, with a general formula of CnH2n-2. Dienes and alkynes are functional isomers...
. During a DAINV reaction, three pi-bonds are broken, and two sigma-bonds and one new pi-bond are formed. A prototypical DAINV reaction is shown on the right.
DAINV reactions often involve heteroatoms, and can be used to form heterocyclic compounds. This makes the DAINV reaction particularly useful in natural product syntheses, where the target compounds often contain heterocycles. Recently, the DAINV reaction has been used to synthesize a drug transport system for treatment of prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
cells.
History
The Diels-Alder reaction was first reported in 1928 by Otto DielsOtto Diels
Otto Paul Hermann Diels was a German chemist. He was the son of a professor of philology at the University of Berlin, where he himself earned his doctorate in chemistry, in the group of Emil Fischer....
and Kurt Alder
Kurt Alder
Kurt Alder was a German chemist and Nobel laureate.-Biography:Alder was born in the industrial area of Königshütte, Silesia , where he received his early schooling...
; they were awarded the Nobel Prize
Nobel Prize
The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...
in chemistry for their work in 1950. Since that time, use of the Diels-Alder reaction has become widespread. Conversely, DAINV does not have a clear date of inception, and lacks the comparative notoriety of the standard Diels-Alder. Much of the work in this area is attributed to Dale Boger, though other authors have published numerous papers on the subject.
Mechanism
Formal MechanismThe mechanism of the DAINV reaction is controversial. While it is accepted as a formal [4+2] cycloaddition
Cycloaddition
A cycloaddition is a pericyclic chemical reaction, in which "two or more unsaturated molecules combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity." The resulting reaction is a cyclization reaction.Cycloadditions are usually described by the...
, it is not well understood whether or not the reaction is truly concerted. The accepted view is that most DAINV reactions occur via an asynchronous mechanism. The reaction proceeds via a single transition state, but not all bonds are formed or broken at the same time, as would be the case in a concerted mechanism.
The formal DAINV mechanism for the reaction of acrolein
Acrolein
Acrolein is the simplest unsaturated aldehyde. It is produced widely but is most often immediately reacted with other products due to its instability and toxicity...
and methyl vinyl ether
Methyl vinyl ether
Methyl vinyl ether is an organic compound with the chemical formula C3H6O. It is the simplest chemical that contains both an alkene group and an alkyl group with an ether linkage. The compound can be made by reaction of acetylene and methanol in presence of a base. The alkene portion of the...
is shown in the figure to the right. Though not entirely accurate, it provides a useful model for the reaction. During the course of the reaction, three pi-bonds (labeled with red) are broken, and three new bonds are formed (labeled in blue): two sigma-bonds and one new pi-bond.
Transition State
Like the standard DA, DAINV reactions proceed via a single boat transition state
Transition state
The transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest energy along this reaction coordinate. At this point, assuming a perfectly irreversible reaction, colliding reactant molecules will always...
, despite not being concerted. The single boat transition state is a simplification, but DFT
DFT
DFT may stand for:*Discrete Fourier transform*Decision field theory*Density functional theory*Demand Flow Technology*The United Kingdom's Department for Transport*Design For Test*Deareating Feed Tank*Digital Film Technology maker of the Spirit DataCine...
calculations suggest that the time difference in bond scission and formation is minimal, and that despite potential asynchronicity, the reaction is concerted, with relevant bonds being either partially broken or partially formed at some point during the reaction. The near synchronicity of the DAINV means it can be treated similarly to the standard Diels-Alder reaction.
The reaction can be modeled using a closed, boat-like transition state, with all bonds being in the process of forming or breaking at some given point, and therefore must obey the Woodward-Hoffman general selection rules. This means that for a three component, six electron system, all components must interact in a suprafacial manner (or one suprafacial and two antarfacial). With all components being suprafacial, the allowed transition state
Transition state
The transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest energy along this reaction coordinate. At this point, assuming a perfectly irreversible reaction, colliding reactant molecules will always...
is boat-like; a chair-like transition state would result in three two-electron antarafacial components. The chair-like case is thermally disallowed by the Woodward-Hoffman rules.
Molecular Orbital Theory
Standard DA ReactionsIn the standard Diels-Alder reaction, there are two components: the diene
Diene
In organic chemistry a diene or diolefin is a hydrocarbon that contains two carbon double bonds.Conjugated dienes are functional groups, with a general formula of CnH2n-2. Dienes and alkynes are functional isomers...
, which is electron rich, and the dienophile, which is electron poor. The relative electron-richness and electron deficiency of the reactants can best be described visually, in a Molecular Orbital Diagram. In the standard Diels-Alder, the electron rich diene
Diene
In organic chemistry a diene or diolefin is a hydrocarbon that contains two carbon double bonds.Conjugated dienes are functional groups, with a general formula of CnH2n-2. Dienes and alkynes are functional isomers...
has molecular orbitals that are higher in energy than the orbitals of the electron poor dienophile. This difference in relative orbital energies means that, of the frontier molecular orbitals
Frontier Molecular Orbital Theory
In chemistry, frontier molecular orbital theory is an application of MO theory describing HOMO / LUMO interactions.- History :In 1952, Kenichi Fukui published a paper in the Journal of Chemical Physics titled "A molecular theory of reactivity in aromatic hydrocarbons." Though widely criticized at...
the HOMO
Homo
Homo may refer to:*the Greek prefix ὅμο-, meaning "the same"*the Latin for man, human being*Homo, the taxonomical genus including modern humans...
of the diene (HOMOdiene) and the LUMO
Lumo
Lumo is a 2007 documentary film about twenty-year-old Lumo Sinai, a woman who fell victim to "Africa's First World War." While returning home one day, Lumo and another woman were gang-raped by a group of soldiers fighting for control of the Democratic Republic of the Congo during the 1994 Rwandan...
of the dienophile (LUMOdienophile) are more similar in energy than the HOMOdienophile and the LUMOdiene. The strongest orbital interaction is between the most similar frontier molecular orbitals: HOMOdiene and LUMOdienophile.
[4+2] Dimerization Reactions
Dimerization reactions are neither normally or inversely accelerated, and are usually low yielding. In this case, two monomers react in a DA fashion. Because the orbital energies are identical, there is no preference for interaction of the HOMO or the LUMO of either the diene or dienophile. The low yield of dimerization reactions is explained my second-order perturbation theory
Perturbation theory
Perturbation theory comprises mathematical methods that are used to find an approximate solution to a problem which cannot be solved exactly, by starting from the exact solution of a related problem...
. The LUMO and HOMO of each species are farther apart in energy in a dimerization than in either normally or inversely accelerated Diels-Alder. This means that the orbitals interact less, and there is a lower thermodynamic drive for dimerization.
Diels-Alder with inverse electron demand
In the dimerization reactions, the diene and dienophile were equally electron rich (or equally electron poor). If the diene becomes any less electron rich, the the dienophile any more so, the possbile [4+2] cycloaddition reaction will then be a DAINV reaction. In the DAINV reaction, the LUMOdiene and HOMOdienophile are closer in energy than the HOMOdiene and LUMOdienophile. Thus, the LUMOdiene and HOMOdienophile are the frontier orbitals that interact the most strongly, and result in the most energetically favourable bond formation.
Regiochemistry and Stereochemistry of DAINV
RegiochemistryRegiochemistry in DAINV reactions can be reliably predicted in many cases. This can be done one of two ways, either by electrostatic (charge) control, or orbital control.
- Charge control:
- Each of the starting materials (diene and dienophile) has a several resonance forms.
- These resonance forms can be used to assign partial charges to each of the atoms.
- Partially negative atoms on the diene will bond to partially positive atoms on the dienophile, and vice versa.
- Orbital control:
- The HOMO of the dienophile reacts with the LUMO of the diene.
- The relative orbital size on each atom is represented by orbital coefficients in the FMO.
- Orbitals will align to maximize the bonding interactions, and minimize the anti-bonding interactions.
Alder-Stein Principle
The Alder-Stein principle states that the stereochemistry of the reactants is maintained in the stereochemistry of the products during a Diels-Alder reaction. This means that groups which were cis in relation to one another in the starting materials will be syn to one another in the product, and groups that were trans to one another in the starting material will be anti in the product.
It is important to note that the Alder-Stein principle has no bearing on the relative orientation of groups on the two starting materials. One cannot predict, via this principle, whether a substituent on the diene will be syn or anti to a substituent on the dienophile. The Alder-Stein principle is only consistent across the self-same starting materials. The relationship is only valid for the groups on the diene alone, or the groups on the dienophile, alone. The relative orientation of groups between the two reactants can be predicted by the endo selection rule.
Endo selection rule
Similarly to the standard Diels-Alder reaction, the DAINV also obeys a general endo selection rule. In the standard Diels-Alder, it is known that electron withdrawing groups on the dienophile will approach endo, with respect to the diene. The exact cause of this selectivity is still debated, but the most accepted view is that endo approach maximizes secondary orbital overlap. The DAINV favors an endo orientation of electron donating substituents on the dienophile.Since all Diels-Alder reactions proceed through a boat transition state
Transition state
The transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest energy along this reaction coordinate. At this point, assuming a perfectly irreversible reaction, colliding reactant molecules will always...
, there is an "inside" and an "outside" of the transition state (inside and outside the "boat"). The substituents on the dienophile are considered "endo" if they are 'inside' the boat, and "exo" if they are on the outside.
The exo pathway would be favored by sterics, so a different explanation is needed to justify the general predominance of endo products. FMO theory can be used to explain this outcome. When the substituents of the dienophile are exo, there is no interaction between those substituents and the diene. However, when the dienophile substituents are endo, there is considerable orbital overlap with the diene. In the case of DAINV the overlap of the orbitals of the electron withdrawing substituents with the orbitals of the diene create a favorable bonding interaction, stabilizing the transition state. The energy of the transition state of a reaction is directly related to the activation energy
Activation energy
In chemistry, activation energy is a term introduced in 1889 by the Swedish scientist Svante Arrhenius that is defined as the energy that must be overcome in order for a chemical reaction to occur. Activation energy may also be defined as the minimum energy required to start a chemical reaction...
. Referring to the Arrhenius equation
Arrhenius equation
The Arrhenius equation is a simple, but remarkably accurate, formula for the temperature dependence of the reaction rate constant, and therefore, rate of a chemical reaction. The equation was first proposed by the Dutch chemist J. H. van 't Hoff in 1884; five years later in 1889, the Swedish...
, the reaction with the lower activation energy will proceed at a greater rate.
Common Dienes
The dienesDienes
Dienes may mean:* People: see Dienes for a list of people with the surname Dienes.* Dienes are a type of chemical compound....
used in Inverse electron demand Diels-Alder are relatively electron-deficient species; compared to the standard Diels-Alder, where the diene is electron rich. These electron-poor species have lower molecular orbital
Molecular orbital
In chemistry, a molecular orbital is a mathematical function describing the wave-like behavior of an electron in a molecule. This function can be used to calculate chemical and physical properties such as the probability of finding an electron in any specific region. The term "orbital" was first...
energies than their standard DA counterparts. This lowered energy results from the inclusion of either: A) electron withdrawing groups, or B) electronegative heteroatoms. Aromatic compounds can also react in DAINV reactions, such as triazines and tetrazines. Other common classes of dienes are oxo
Oxo
OXO was the first digital graphical computer game, a version of Tic-tac-toe.It is also the first puzzler game; As seen on Ginuess World Records 2010 Gamer's Edition.OXO Was first released in 1951, That makes it one of the oldest games standing....
- and aza
Aza
Aza may refer to:*Gaza*Gaza Strip*Aza , a village or town section in the Japanese addressing system*Azadkənd, Nakhchivan, Azerbaijan*Aza, Azerbaijan*Aźa, a Tibetan name for the Tuyuhun Kingdom...
- butadienes.
The key quality of a good DAINV diene is a significantly lowered HOMO and LUMO, as compared to standard DA dienes. Below is a table showing a few commonly used DAINV dienes, their HOMO and LUMO energies, and some standard DA dienes, along with their respective MO energies.
| Diene | Name | HOMO Energy (eV) | LUMO Energy (eV) |
|---|---|---|---|
| 2-cyclohexylidene-3-oxo-3-phenylpropanenitrile | -9.558 | 2.38 | |
| Acrolein | -14.5 | 2.5 | |
| 5-cyclopentylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione | -10.346 | 1.879 | |
| Butadiene | -10.346 | 1.879 | |
| 1-Methoxy-butadiene | -8.21 | 3.77 | |
| 2,3-dimethyl-butadiene | -8.76 | 2.18 |
Common Dienophiles
The dienophiles used in Inverse electron demand Diels-Alder reactions are, unlike in the standard DA, very electron rich, containing one or more electron donating groups. This results in higher orbital energies, and thus more orbital overlap with the LUMO of the diene. Common classes of dieneophiles for DAINV reaction include vinyl ethers and vinyl acetals, imine, enamines, alkynes and highly strained olefins.The most important consideration in choice of dienophile is its relative orbital energies. Both HOMO and LUMO impact the rate and selectivity of the reaction. A table of common DAINV dienophiles, standard DA dienophiles, and their respective MO energies can be seen below.
| Dienophile | Name | HOMO Energy (eV) | LUMO Energy (eV) |
|---|---|---|---|
| ethyl vinyl ether | -9..006 | 5.313 | |
| 2-methylenetetrahydro-2H-pyran | -8.939 | 5.140 | |
| 1,1'-bis(cyclopentilidene) | -8.242 | 4.749 | |
| Acrolein | -14.5 | 2.5 | |
| Cyclohexene | -8.94 | 2.1 | |
| Propene | -9.13 | 1.8 | |
| Ethylene | -10.52 | 1.5 |
A second table shows how electron richness in the dienophiles affects the rate of reaction with a very electron poor diene, namely hexachlorocyclopentadiene
Hexachlorocyclopentadiene
Hexachlorocyclopentadiene is an organochlorine compound that is a precursor to several pesticides. This colourless liquid is an inexpensive reactive diene. Many of its derivatives proved to be highly controversial, as studies showed them to be persistent organic pollutants. Collectively, the...
.
| Dienophile | Relative Reaction Rate with Hexachlorocyclopentadiene |
|---|---|
| Cyclopentadiene | 15200 |
| p-Methoxystyrene | 1580 |
| Styrene | 750 |
| p-Nitrostyrene | 538 |
| 2,3-Dihydrofuran | 333 |
| Norbornene | 70.8 |
| Cyclopentene | 59.0 |
| Maleic Anhydride | 29.1 |
| Cyclohexene | 3.0 |
Scope and Applications
DAINV reactions provide a pathway to a rich library of synthetic targets, and have been utilized to form many highly functionalized systems, including selectively protected sugars, an important contribution to the field of sugar chemistry. In addition, DAINV reactions can produce an array of different products from a single starting material, such as tetrazine.DAINV reactions have been utilized for the synthesis of several natural products, including (-)-CC-1065, a parent compound in the Duocarmycin
Duocarmycin
The duocarmycins are a series of related natural products first isolated from Streptomyces bacteria in 1988. They were found to have potent antitumor properties....
series, which found use as an anticancer treatment. Several drug candidates in this series have progress into clinical trials. The DAINV reaction was used to synthesise the PDE-I and PDE-II sections of (-)-CC-1065. The first reaction in the sequence is a DAINV reaction between the tetrazine
Tetrazine
Tetrazine is an unstable compound that consists of a six-membered aromatic ring containing four nitrogen atoms with the molecular formula C2H2N4. The name tetrazine is used in the nomenclature of derivatives of this compound...
and vinyl acetal, followed by a retro Diels-Alder to afford a 1,2-diazine
Diazine
Diazine refers to a group of organic compounds having the molecular formula C4H4N2. Each contains a benzene ring in which two of the C-H fragments have been replaced by isolobal nitrogen...
product. After several more steps, an intramolecular
Intramolecular
Intramolecular in chemistry describes a process or characteristic limited within the structure of a single molecule, a property or phenomenon limited to the extent of a single molecule.- Examples :...
DA,sub>INV reaction occurs, followed again by a retro Diels-Alder in situ, to afford an indoline
Indoline
Indoline is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing ring. The compound is based on the indole structure, but the 2-3 bond is saturated. by oxidation/dehydrogenation it can be...
product. This indoline is a converted into either PDE-I or PDE-II in a few synthetic steps.
See also
- Diels-Alder ReactionDiels-Alder reactionThe Diels–Alder reaction is an organic chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. The reaction can proceed even if some of the atoms in the newly formed ring are not carbon...
- CycloadditionCycloadditionA cycloaddition is a pericyclic chemical reaction, in which "two or more unsaturated molecules combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity." The resulting reaction is a cyclization reaction.Cycloadditions are usually described by the...
- Pericyclic Reaction
- Molecular Orbital TheoryMolecular orbital theoryIn chemistry, molecular orbital theory is a method for determining molecular structure in which electrons are not assigned to individual bonds between atoms, but are treated as moving under the influence of the nuclei in the whole molecule...