Juliá-Colonna epoxidation
Encyclopedia
The Juliá-Colonna epoxidation is an asymmetric poly-leucine
catalyzed nucleophilic epoxidation
of electron deficient olefins in a triphasic system
. The reaction was first developed by Sebastian Juliá (lnstituto Qulmico de Sarriá, Barcelona, Spain) in 1980 (published), and the first article was followed up in 1982 with further elaboration by both Juliá and Stefano Colonna (lstituto di Chimica Industriale dell'Università, Milan, Italy.)
In the original triphasic protocol, the chalcone
substrate is soluble in the organic phase, generally toluene
or carbon tetrachloride
. The alkaline hydrogen peroxide oxidant is soluble primarily in the aqueous phase, and the reaction occurs at the insoluble polymer layer at the interface of the two phases. Alternative biphasic
and monophasic protocols have been developed with increased substrate accessibility and reaction rate.
The efficient enantioselective catalytic epoxidation under mild conditions is of great synthetic utility. Not only are epoxides effective synthons for a range of transformations, they have a significant presence in natural products structures. Furthermore, the reaction has been effectively scaled up to industrially useful levels, with work conducted notably by Bayer and Evonik. Finally, the enzyme-like activity of the poly-amino acid segments is suggestive of a role of the reaction in the prebiotic origin of life
.
of electron-deficient olefins such as α,β-unsaturated ketones. The general mechanism shown in Figure 2 applies to all nucleophilic epoxidations but is controlled in this reaction by the poly-leucine catalyst.
The hydroperoxide anion and chalcone assemble in a complex with the poly-leucine catalyst before reacting to form a peroxide enolate intermediate. The intermediate subsequently closes, as controlled by the catalyst structure, to form the epoxide product stereoselectively.
The poly-leucine strands demonstrate enzyme-like kinetics
with a first-order dependence on and eventual saturation with both the hydroperoxide anion (KM= 30 mM) and the olefin substrate (KM=110 mM.) Kinetic study suggests that the reaction proceeds by random steady-state formation of a ternary (polyleucine+hydroperoxide anion+olefin) complex
. Both substrates must bind prior to reaction, and while either may bind first, initial hydroperoxide binding is kinetically preferred. The rapid equilibrium enabling complex formation is followed by the rate-limiting formation of the peroxide enolate (Figure 3).
. While other models have been proposed, computations by Kelly et al. have suggested that the NH-2, NH-3, and NH-4 form an isosceles triangle available for hydrogen bonding as an intermediate-stabilizing oxyanion hole. While olefin binding to either the endo or exo face of the helix is sterically allowed, only endo binding orients the NH-4 group to bind with the hydroperoxide moiety allowing for hydroxide displacement in the final reaction step (Figure 4).
and poly-alanine
. Both poly-L- and poly-D-amino acids are available and cause the opposite stereoinduction.
Especially in biphasic systems, reaction time may be reduced and enantioselectivity increased by activating the catalyst with NaOH prior to reaction. Furthermore, in biphasic systems, the polymer may be immobilized on polystyrene
, polyethylene glycol
(PEG), or silica gel and formed into a paste.
structure where the four to five N-terminal residues are actively involved in catalysis. While active catalysts have been generated from scalemic leucine, consistent enantiomeric
content must be maintained through the N-terminal region to give appropriate handedness to the structure. While the greatest enantioselectivity was originally observed when n=30 residues, a 10-mer Leucine polypeptide is of sufficient length to provide significant enantioselectivity Following improvement of the original procedure, greater enantioselectivity has been observed for lower molecular weight polymers, presumably due to the greater number of N-termini available per mass used.
substrates, and the scope of the reaction is being expanded with further methdological investigation.
Several classes of substrates, however, are not suitable for the Juliá-Colonna Epoxidation. These include:
The nucleophilic epoxidation is naturally complementary in scope to electrophilic epoxidations such as the Sharpless epoxidation
and Jacobsen epoxidation.
Chiral amino acids, including leucine, have been generated in electrical discharge experiments designed to mimic the prebiotic conditions on Earth, and they have been found in scalemic mixtures in meteorites. It has been suggested that poly-amino acid fragments analogous to the Juliá-Colonna catalyst may have been initiated by imidazole
or cyanide
derivatives, and the resulting fragments may have played a catalytic role in the origin of enantiomeric enrichment ubiquitous in life today.
(THF) along with the urea
hydrogen peroxide
(UHP) oxidant and a tertiary amine base such as 8-diazabicyclo[5.4.0]undec-7-ene (DBU.) The immobilized polymer catalyst forms a paste which serves as the reaction site. The two phase reaction conditions extended the range of enones to which the reaction could be applied.
. Utilization of this catalyst in homogeneous reaction conditions enabled marked extension of the methodology to α,β-unsaturated ketones, dienes
, and bis-dienes.
dramatically increases the rate of reaction. The co-catalyst is presumed to increase the concentration of the peroxide oxidant in the organic phase enabling more efficient access to the reactive ternary complex. These conditions were developed for application to two phase systems but also function for three phase systems and have been utilized up to the 100g scale
s and are being investigated for application to continuous flow fixed bed reactors.
(Figure 6.) Diltiazem is a commercially available pharmaceutical which acts as a calcium channel
blocker.
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
catalyzed nucleophilic epoxidation
Epoxide
An epoxide is a cyclic ether with three ring atoms. This ring approximately defines an equilateral triangle, which makes it highly strained. The strained ring makes epoxides more reactive than other ethers. Simple epoxides are named from the parent compound ethylene oxide or oxirane, such as in...
of electron deficient olefins in a triphasic system
Liquid-liquid extraction
Liquid–liquid extraction, also known as solvent extraction and partitioning, is a method to separate compounds based on their relative solubilities in two different immiscible liquids, usually water and an organic solvent. It is an extraction of a substance from one liquid phase into another liquid...
. The reaction was first developed by Sebastian Juliá (lnstituto Qulmico de Sarriá, Barcelona, Spain) in 1980 (published), and the first article was followed up in 1982 with further elaboration by both Juliá and Stefano Colonna (lstituto di Chimica Industriale dell'Università, Milan, Italy.)
In the original triphasic protocol, the chalcone
Chalcone
Chalcone is an aromatic ketone and an enone that forms the central core for a variety of important biological compounds, which are known collectively as chalcones or chalconoids.-Chemical synthesis:...
substrate is soluble in the organic phase, generally toluene
Toluene
Toluene, formerly known as toluol, is a clear, water-insoluble liquid with the typical smell of paint thinners. It is a mono-substituted benzene derivative, i.e., one in which a single hydrogen atom from the benzene molecule has been replaced by a univalent group, in this case CH3.It is an aromatic...
or carbon tetrachloride
Carbon tetrachloride
Carbon tetrachloride, also known by many other names is the organic compound with the formula CCl4. It was formerly widely used in fire extinguishers, as a precursor to refrigerants, and as a cleaning agent...
. The alkaline hydrogen peroxide oxidant is soluble primarily in the aqueous phase, and the reaction occurs at the insoluble polymer layer at the interface of the two phases. Alternative biphasic
Biphasic
A biphasic system is one which has two phases.* In the physical sciences, a liquid water and steam system would represent a biphasic system. See phase ....
and monophasic protocols have been developed with increased substrate accessibility and reaction rate.
The efficient enantioselective catalytic epoxidation under mild conditions is of great synthetic utility. Not only are epoxides effective synthons for a range of transformations, they have a significant presence in natural products structures. Furthermore, the reaction has been effectively scaled up to industrially useful levels, with work conducted notably by Bayer and Evonik. Finally, the enzyme-like activity of the poly-amino acid segments is suggestive of a role of the reaction in the prebiotic origin of life
Abiogenesis
Abiogenesis or biopoesis is the study of how biological life arises from inorganic matter through natural processes, and the method by which life on Earth arose...
.
Reaction mechanism
The Juliá-Colonna epoxidation is an asymmetric nucleophilic epoxidationAsymmetric nucleophilic epoxidation
Nucleophilic epoxidation is the formation of epoxides from electron-deficient double bonds through the action of nucleophilic oxidants. Nucleophilic epoxidation methods represent a viable alternative to electrophilic methods, many of which do not epoxidize electron-poor double bonds...
of electron-deficient olefins such as α,β-unsaturated ketones. The general mechanism shown in Figure 2 applies to all nucleophilic epoxidations but is controlled in this reaction by the poly-leucine catalyst.
The hydroperoxide anion and chalcone assemble in a complex with the poly-leucine catalyst before reacting to form a peroxide enolate intermediate. The intermediate subsequently closes, as controlled by the catalyst structure, to form the epoxide product stereoselectively.
Ternary complex formation
The poly-leucine strands demonstrate enzyme-like kinetics
Enzyme kinetics
Enzyme kinetics is the study of the chemical reactions that are catalysed by enzymes. In enzyme kinetics, the reaction rate is measured and the effects of varying the conditions of the reaction investigated...
with a first-order dependence on and eventual saturation with both the hydroperoxide anion (KM= 30 mM) and the olefin substrate (KM=110 mM.) Kinetic study suggests that the reaction proceeds by random steady-state formation of a ternary (polyleucine+hydroperoxide anion+olefin) complex
Ternary complex
A Ternary complex refers to a protein complex containing three different molecules which are bound together. In structural biology ternary complex can be used to describe a crystal containing a protein with two small molecules bound, for example cofactor and substrate; or a complex formed between...
. Both substrates must bind prior to reaction, and while either may bind first, initial hydroperoxide binding is kinetically preferred. The rapid equilibrium enabling complex formation is followed by the rate-limiting formation of the peroxide enolate (Figure 3).
Mechanistic origin of stereoselectivity
All of the reactants associate with the polyleucine catalyst prior to reaction to form the hydroperoxide enolate intermediate. The catalyst orients the reactants and, even more significantly, the peroxide enolate intermediate by a series of hydrogen bonding interactions with the four N-terminal amino groups in the poly-leucine α-helixAlpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
. While other models have been proposed, computations by Kelly et al. have suggested that the NH-2, NH-3, and NH-4 form an isosceles triangle available for hydrogen bonding as an intermediate-stabilizing oxyanion hole. While olefin binding to either the endo or exo face of the helix is sterically allowed, only endo binding orients the NH-4 group to bind with the hydroperoxide moiety allowing for hydroxide displacement in the final reaction step (Figure 4).
Poly-amino acid Selection
Enantioselectivity is maximized by poly-amino acid sequences containing the greatest α-helical content; these include poly-leucineLeucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
and poly-alanine
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
. Both poly-L- and poly-D-amino acids are available and cause the opposite stereoinduction.
Catalyst generation
The original poly-leucine catalysts were formed by reacting leucine-N-carboxyanhydrides with an initiator such as an amine, an alcohol or water (Figure 5). In triphasic systems, the polymer catalyst must be soaked in the organic solvent and peroxide solution to generate a gel prior to reaction.Especially in biphasic systems, reaction time may be reduced and enantioselectivity increased by activating the catalyst with NaOH prior to reaction. Furthermore, in biphasic systems, the polymer may be immobilized on polystyrene
Polystyrene
Polystyrene ) also known as Thermocole, abbreviated following ISO Standard PS, is an aromatic polymer made from the monomer styrene, a liquid hydrocarbon that is manufactured from petroleum by the chemical industry...
, polyethylene glycol
Polyethylene glycol
Polyethylene glycol is a polyether compound with many applications from industrial manufacturing to medicine. It has also been known as polyethylene oxide or polyoxyethylene , depending on its molecular weight, and under the tradename Carbowax.-Available forms:PEG, PEO, or POE refers to an...
(PEG), or silica gel and formed into a paste.
Catalyst Secondary Structure
The active component of the catalyst assumes an α-helicalAlpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
structure where the four to five N-terminal residues are actively involved in catalysis. While active catalysts have been generated from scalemic leucine, consistent enantiomeric
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
content must be maintained through the N-terminal region to give appropriate handedness to the structure. While the greatest enantioselectivity was originally observed when n=30 residues, a 10-mer Leucine polypeptide is of sufficient length to provide significant enantioselectivity Following improvement of the original procedure, greater enantioselectivity has been observed for lower molecular weight polymers, presumably due to the greater number of N-termini available per mass used.
Scope
The Juliá-Colonna Epoxidation of electron-deficient olefins was originally demonstrated with chalcones, but it was soon extended to other systems with electron withdrawing moieties such as α,β-unsaturated ketones, esters, and amides. The reaction has also demonstrated efficiency with sulfoneSulfone
A sulfone is a chemical compound containing a sulfonyl functional group attached to two carbon atoms. The central hexavalent sulfur atom is double bonded to each of two oxygen atoms and has a single bond to each of two carbon atoms, usually in two separate hydrocarbon substituents.-IUPAC name and...
substrates, and the scope of the reaction is being expanded with further methdological investigation.
Several classes of substrates, however, are not suitable for the Juliá-Colonna Epoxidation. These include:
- compounds sensitive to hydroxide.
- compounds with acidic protons on the α or α’ positions.
- electron rich olefins.
The nucleophilic epoxidation is naturally complementary in scope to electrophilic epoxidations such as the Sharpless epoxidation
Sharpless epoxidation
The Sharpless Epoxidation reaction is an enantioselective chemical reaction to prepare 2,3-epoxyalcohols from primary and secondary allylic alcohols....
and Jacobsen epoxidation.
Jacobsen epoxidation
The Jacobsen Epoxidation, sometimes also referred to as Jacobsen-Katsuki Epoxidation is a chemical reaction which allows enantioselective epoxidation of unfunctionalized alkyl- and aryl- substituted olefins. It is complementary to the Sharpless epoxidation...
Catalyst structure
The stereoinduction of the Juliá-Colonna epoxidation is dependent on the α-helical secondary structure of the poly-leucine catalyst. While the consistent stereochemistry of the N-terminal amino acids is necessary for this induction, even a 10-mer leucine polypeptide is of sufficient length to provide significant enantioselectivity.Chiral amplification by scalemic catalysts
This dependence solely on the N-terminal region of the helix is most pronounced in enantioselective stereoinduction by scalemic catalysts. Even a 40% enantiomeric excess of L vs. D-leucine in catalyst formation can yield the same enantiomeric enriched epoxide as the enantiopure catalyst. The relationship between catalyst and product enantiopurity can be closely approximated with a Bernoullian statistical model: een=(Ln-Dn)/(Ln+Dn) where L and D are the proportions of L- and D-leucine used to generate the catalytic polymers and n is the length of the catalytic component.Chiral amino acids, including leucine, have been generated in electrical discharge experiments designed to mimic the prebiotic conditions on Earth, and they have been found in scalemic mixtures in meteorites. It has been suggested that poly-amino acid fragments analogous to the Juliá-Colonna catalyst may have been initiated by imidazole
Imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...
or cyanide
Cyanide
A cyanide is a chemical compound that contains the cyano group, -C≡N, which consists of a carbon atom triple-bonded to a nitrogen atom. Cyanides most commonly refer to salts of the anion CN−. Most cyanides are highly toxic....
derivatives, and the resulting fragments may have played a catalytic role in the origin of enantiomeric enrichment ubiquitous in life today.
Silica-grafted catalysts
Silica-grafted polyleucine has been shown to effectively catalyze epoxidation of α,β-unsaturated aromatic ketones. The silica graft allows for the catalyst to be easily recovered with only mild loss of activity and is particularly useful for scale-up reactions.Biphasic (non-aqueous) reaction conditions
For the alternative biphasic protocol, the olefin substrate is dissolved in tetrahydrofuranTetrahydrofuran
Tetrahydrofuran is a colorless, water-miscible organic liquid with low viscosity at standard temperature and pressure. This heterocyclic compound has the chemical formula 4O. As one of the most polar ethers with a wide liquid range, it is a useful solvent. Its main use, however, is as a precursor...
(THF) along with the urea
Urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
hydrogen peroxide
Organic peroxide
Organic peroxides are organic compounds containing the peroxide functional group . If the R' is hydrogen, the compound is called an organic hydroperoxide. Peresters have general structure RCOOR. The O-O bond easily breaks and forms free radicals of the form RO·...
(UHP) oxidant and a tertiary amine base such as 8-diazabicyclo[5.4.0]undec-7-ene (DBU.) The immobilized polymer catalyst forms a paste which serves as the reaction site. The two phase reaction conditions extended the range of enones to which the reaction could be applied.
Monophasic reaction conditions with PEG-immobilized polyleucine
A soluble initiator O,O′-bis(2-aminoethyl)polyethylene glycol (diaminoPEG) for poly-leucine assembly was utilized to generate a THF-soluble triblock polymerPolymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
. Utilization of this catalyst in homogeneous reaction conditions enabled marked extension of the methodology to α,β-unsaturated ketones, dienes
Dienes
Dienes may mean:* People: see Dienes for a list of people with the surname Dienes.* Dienes are a type of chemical compound....
, and bis-dienes.
Phase transfer co-catalysis
Addition of tetrabutylammonium bromide as a phase transfer catalystPhase transfer catalyst
In chemistry, a phase transfer catalyst or PTC is a catalyst that facilitates the migration of a reactant from one phase into another phase where reaction occurs. Phase transfer catalysis is a special form of heterogeneous catalysis. Ionic reactants are often soluble in an aqueous phase but...
dramatically increases the rate of reaction. The co-catalyst is presumed to increase the concentration of the peroxide oxidant in the organic phase enabling more efficient access to the reactive ternary complex. These conditions were developed for application to two phase systems but also function for three phase systems and have been utilized up to the 100g scale
Scale-up
Immobilized catalysts have been used in membrane reactorMembrane reactor
A membrane reactor is a piece of chemical equipment that combines a catalyst-filled reaction chamber with a membrane to add reactants or remove products of the reaction.Chemical reactors making use of membranes are usually referred to as membrane reactors...
s and are being investigated for application to continuous flow fixed bed reactors.
Total synthesis of Diltiazem
Adger et al. utilized the biphasic Juliá-Colonna Epoxidation with immobilized poly-L-leucine (I-PLL) and urea hydrogen peroxide (UHP), and 8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the key step in the efficient synthesis of DiltiazemDiltiazem
Diltiazem is a non-dihydropyridine member of the class of drugs known as calcium channel blockers, used in the treatment of hypertension, angina pectoris, and some types of arrhythmia....
(Figure 6.) Diltiazem is a commercially available pharmaceutical which acts as a calcium channel
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
blocker.