Wender Taxol total synthesis
Encyclopedia
The Wender Taxol total synthesis in organic chemistry
describes a Taxol total synthesis
(one of six to date) by the group of Paul A. Wender at Stanford University
published in 1997. This synthesis has much in common with the Holton Taxol total synthesis
in that it is a linear synthesis starting from a naturally occurring compound with ring construction in the order A,B,C,D. The Wender effort is shorter by approximately 10 steps.
Raw materials for the preparation of Taxol by this route include verbenone
, prenyl bromine, allyl bromide
, propiolic acid
, Gilman reagent
, and Eschenmoser's salt
.
1 in Scheme 1, which is the oxidation product of naturally occurring α-pinene
and forming ring A. Construction of ring B started with abstraction
of the vinylic enone
proton by potassium tert-butoxide
followed by nucleophilic displacement of the bromine
atom in prenyl bromide 2 to formdiene
3. Ozonolysis
of the prenyl group (more electron-rich than the internal double bond) formed aldehyde
4, which, after isomerization or photorearrangement to the Chrysanthenone
5, was reacted with the lithium salt (via LDA
) of the ethyl ester
of Propiolic acid
6 in a nucleophilic addition
to the alcohol
7. This compound was not isolated but trapped
in situ
with trimethylsilyl chloride
to the silyl ether
8. In the next step, Gilman reagent
9 is a methylating reagent
in nucleophilic conjugate addition
through the alkyne
group to the ketone
group, which formed the alcohol
10. The silyl ether protective group was removed by reaction with acetic acid
to alcohol 11, which was then oxidized to the ketone
12 with RuCl2(PPh3)3
and NMO
as the sacrificial catalyst. The acyloin
group in 13 was introduced by KHMDS
and Davis’ oxaziridine
(see Holton Taxol total synthesis
for another use of this system) and its hydroxyl group together with the ester group were reduced by lithium aluminium hydride
to tetrol 14. Finally, the primary alcohol group was protected as a tert-butyldimethylsilyl ether
by the corresponding silylchloride and imidazole
in triol 15.
In the second part (Scheme 2) the procedures are still confined to rings A and B. More protective groups were added to triol 15 as reaction with PPTS and 2-methoxypropene gives the acetonide 16. At this point the double bond in ring A was epoxidized with m-CPBA and sodium carbonate
to epoxide
17 and a Grob fragmentation
(also present in the Holton effort) initiated by DABCO
opened up the AB ring system in alcohol 18, which was not isolated but protected as a TIPS silyl ether
19 with triisopropylsilyl triflate and 2,6-lutidine
. The C1 position was next oxidized by the phosphite ester
, P(OEt)3 and the strong base KOt-Bu, and oxygen to alcohol 20 (the stereochemistry controlled by bowl-shaped AB ring with hydroxylation from unhindered convex direction), the primary alcohol group was deprotected with ammonium chloride
in methanol
to diol
21 and two reductions first with NaBH4
to triol 22 and then hydrogen gas
and Crabtree's catalyst
give triol 23. These positions were protected by trimethylsilyl chloride
and pyridine
to 24 and then triphosgene
to 25 in order to facilitate the oxidation of the primary alcohol group to the aldehyde
26 by PCC
.
27 in a Wittig reaction
with Methoxymethylenetriphenylphosphine
(Scheme 3). The acetonide group was removed by dilute hydrochloric acid
and sodium iodide
in dioxane and one hydroxyl group in the resulting diol 28 was protected as the triethylsilyl ether (TES) 29 with the corresponding silyl chloride and pyridine
enabling oxidation of the remaining hydroxyl group to the ketone
30 with the Dess-Martin periodinane
. Reaction with Eschenmoser's salt
placed a methylene
group (C20 in the Taxol framework) in the alpha position of the aldehyde to 31 and the next reaction introduced (the still lacking) C6 and C7 as the Grignard reagent of allyl bromide
in a nucleophilic addition
aided by zinc(II) chloride, which blocked the Grignard from attack on carbonate group, to alcohol 32. The newly formed alcohol was protected as the BOM ether 33 with BOMCl and N,N-diisopropylethylamine. After removal of the TES protecting group with ammonium fluoride
, the carbonate
group in 34 was converted to a hydroxybenzoate group by action of phenyllithium
and the secondary alcohol to the acetate
35 by in situ
reaction with acetic anhydride
and DMAP. In the next step the acyloin
group had its positions swapped by reaction with triazabicyclodecene
(other amine bases fail) forming 36 and in the final steps ring closure of ring C was accomplished by ozonolysis
at the allyl group to 37 and Aldol reaction
with 4-pyrrolidinopyridine to 38.
ring D starting with protection of the alcohol group in 38 (Scheme 4). as a TROC alcohol 39 with 2,2,2-trichloroethyl chloroformate and pyridine
. The OBOM group was replaced by a bromine
group in three steps: deprotection to 40 with hydrochloric acid
and sodium iodide
, mesylation to 41 with mesyl chloride, DMAP and pyridine
and nucleophilic substitution
with inversion of configuration with lithium bromide
to bromide 42. Because the oxidation of the alkene
group to the diol
43 with osmium tetroxide was accompanied by the undesired migration of the benzoate group, this step was taken to completion with imidazole
as 44. Two additional countermeasures were required: reprotection of the diol as the carbonate ester
45 with triphosgene
and removal of the benzoate group (KCN) to alcohol 46 in preparation of the actual ring closure to the oxetane 47 with N,N-diisopropylethylamine. In the final steps the tertiary alcohol was acylated in 48, the TIPS group removed in 49 and the benzoate group re-introduced in 50.
Tail addition of the Ojima lactam
51 was not disclosed in detail but finally taxol 52 was formed in several steps similar to the other efforts.
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
describes a Taxol total synthesis
Taxol total synthesis
Paclitaxel total synthesis in organic chemistry is a major ongoing research effort in the total synthesis of paclitaxel . This diterpenoid is an important drug in the treatment of cancer but also expensive because the compound is harvested from a scarce resource, namely the Pacific yew...
(one of six to date) by the group of Paul A. Wender at Stanford University
Stanford University
The Leland Stanford Junior University, commonly referred to as Stanford University or Stanford, is a private research university on an campus located near Palo Alto, California. It is situated in the northwestern Santa Clara Valley on the San Francisco Peninsula, approximately northwest of San...
published in 1997. This synthesis has much in common with the Holton Taxol total synthesis
Holton Taxol total synthesis
The Holton Taxol total synthesis, published by Robert A. Holton and his group at Florida State University in 1994 was the first total synthesis of Taxol ....
in that it is a linear synthesis starting from a naturally occurring compound with ring construction in the order A,B,C,D. The Wender effort is shorter by approximately 10 steps.
Raw materials for the preparation of Taxol by this route include verbenone
Verbenone
Verbenone is a natural organic compound classified as a terpene which is found naturally in a variety of plants. The chemical has a pleasant characteristic odor. Besides being a natural constituent of plants, it and its analogs are insect pheromones...
, prenyl bromine, allyl bromide
Allyl bromide
Allyl bromide is an organic halide. Its refractive index is 1.4697 . Allyl bromide is an alkylating agent used in synthesis of polymers, pharmaceuticals, allyls and other organic compounds. Physically, allyl bromide is a clear liquid with an intense, acrid, and persistent smell...
, propiolic acid
Propiolic acid
Propiolic acid, or acetylene mono-carboxylic acid, is an unsaturated organic acid prepared by boiling acetylenedicarboxylic acid, obtained by the action of alcoholic potash on dibromosuccinic acid, or its acid potassium salt with water. It forms silky crystals which melt at 9 °C, and boil at about...
, Gilman reagent
Gilman reagent
A Gilman reagent is a lithium and copper reagent compound, R2CuLi, where R is an organic radical. These are useful because they react with organic chlorides, bromides, and iodides to replace the halide group with an R group. This is extremely useful in creating larger molecules from smaller...
, and Eschenmoser's salt
Eschenmoser's salt
Eschenmoser's salt, dimethylmethylideneammonium iodide, is a strong dimethylaminomethylating agent, used to prepare derivatives of the type RCH2N2. Enolates, enolsilylethers, and even more acidic ketones undergo efficient dimethylaminomethylation...
.
AB Ring synthesis
The taxol synthesis started from the terpene verbenoneVerbenone
Verbenone is a natural organic compound classified as a terpene which is found naturally in a variety of plants. The chemical has a pleasant characteristic odor. Besides being a natural constituent of plants, it and its analogs are insect pheromones...
1 in Scheme 1, which is the oxidation product of naturally occurring α-pinene
Alpha-Pinene
α-Pinene is an organic compound of the terpene class, one of two isomers of pinene. It is an alkene and it contains a reactive four-membered ring. It is found in the oils of many species of many coniferous trees, notably the pine. It is also found in the essential oil of rosemary...
and forming ring A. Construction of ring B started with abstraction
Deprotonation
Deprotonation is the removal of a proton from a molecule, forming the conjugate base.The relative ability of a molecule to give up a proton is measured by its pKa value. A low pKa value indicates that the compound is acidic and will easily give up its proton to a base...
of the vinylic enone
Enone
An enone is an unsaturated chemical compound or functional group consisting of a conjugated system of an alkene and a ketone. The simplest enone is methyl vinyl ketone or CH2=CHCOCH3....
proton by potassium tert-butoxide
Potassium tert-butoxide
Potassium tert-butoxide is the chemical compound with the formula 3COK. This colourless solid is a strong base useful in organic synthesis. It exists as a tetrameric cubane-like cluster...
followed by nucleophilic displacement of the bromine
Bromine
Bromine ") is a chemical element with the symbol Br, an atomic number of 35, and an atomic mass of 79.904. It is in the halogen element group. The element was isolated independently by two chemists, Carl Jacob Löwig and Antoine Jerome Balard, in 1825–1826...
atom in prenyl bromide 2 to formdiene
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...
3. Ozonolysis
Ozonolysis
Ozonolysis is the cleavage of an alkene or alkyne with ozone to form organic compounds in which the multiple carbon–carbon bond has been replaced by a double bond to oxygen...
of the prenyl group (more electron-rich than the internal double bond) formed aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
4, which, after isomerization or photorearrangement to the Chrysanthenone
Chrysanthenone
Chrysanthenone is a terpene. It can be produced from its isomer verbenone in a photochemical rearrangement reaction.-External links:*...
5, was reacted with the lithium salt (via LDA
Lithium diisopropylamide
Lithium diisopropylamide is the chemical compound with the formula [2CH]2NLi. Generally abbreviated LDA, it is a strong base used in organic chemistry for the deprotonation of weakly acidic compounds. The reagent has been widely accepted because it is soluble in non-polar organic solvents and it...
) of the ethyl ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
of Propiolic acid
Propiolic acid
Propiolic acid, or acetylene mono-carboxylic acid, is an unsaturated organic acid prepared by boiling acetylenedicarboxylic acid, obtained by the action of alcoholic potash on dibromosuccinic acid, or its acid potassium salt with water. It forms silky crystals which melt at 9 °C, and boil at about...
6 in a nucleophilic addition
Nucleophilic addition
In organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....
to the alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
7. This compound was not isolated but trapped
Chemical trap
In chemistry, a chemical trap is a chemical compound that is used to detect a certain molecule when* The concentration of this molecule is very small and below detection limit...
in situ
In situ
In situ is a Latin phrase which translated literally as 'In position'. It is used in many different contexts.-Aerospace:In the aerospace industry, equipment on board aircraft must be tested in situ, or in place, to confirm everything functions properly as a system. Individually, each piece may...
with trimethylsilyl chloride
Trimethylsilyl chloride
Trimethylsilyl chloride, also known as chlorotrimethylsilane is a silyl halide, with a variety of different uses in chemistry. It has the formula 3SiCl, and under standard conditions it is a colourless liquid, which is stable in the absence of water...
to the silyl ether
Silyl ether
Silyl ethers are a group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl group. Silyl ethers are usually used as protecting groups for alcohols in organic synthesis...
8. In the next step, Gilman reagent
Gilman reagent
A Gilman reagent is a lithium and copper reagent compound, R2CuLi, where R is an organic radical. These are useful because they react with organic chlorides, bromides, and iodides to replace the halide group with an R group. This is extremely useful in creating larger molecules from smaller...
9 is a methylating reagent
Alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion or a carbene . Alkylating agents are widely used in chemistry because the alkyl group is probably the most common group encountered in...
in nucleophilic conjugate addition
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 polarity, unless the alkene is activated with special...
through the alkyne
Alkyne
Alkynes are hydrocarbons that have a triple bond between two carbon atoms, with the formula CnH2n-2. Alkynes are traditionally known as acetylenes, although the name acetylene also refers specifically to C2H2, known formally as ethyne using IUPAC nomenclature...
group to the ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
group, which formed the alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
10. The silyl ether protective group was removed by reaction with acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
to alcohol 11, which was then oxidized to the ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
12 with RuCl2(PPh3)3
Ruthenium(III) chloride
Ruthenium chloride is the chemical compound with the formula RuCl3. "Ruthenium chloride" more commonly refers to the hydrate RuCl3·xH2O. Both the anhydrous and hydrated species are dark brown or black solids...
and NMO
N-Methylmorpholine N-oxide
N-Methylmorpholine-N-oxide, NMO or NMMO is an organic compound. This heterocyclic amine oxide and morpholine derivative is used in organic chemistry as a co-oxidant and sacrificial catalyst in oxidation reactions for instance in osmium tetroxide oxidations and the Sharpless asymmetric...
as the sacrificial catalyst. The acyloin
Acyloin
Acyloins are a class of organic compounds in organic chemistry sharing a common functional group consisting of a hydroxyl group placed on the α-position of a carbonyl group.- Nomenclature :Common types of ketols include:...
group in 13 was introduced by KHMDS
Sodium bis(trimethylsilyl)amide
Sodium bisamide is the chemical compound with the formula 2NNa. This species, usually called NaHMDS , is a strong base used for deprotonation reactions or base catalyzed reaction...
and Davis’ oxaziridine
Oxaziridine
An oxaziridine is an organic molecule that features a three-membered heterocycle containing oxygen, nitrogen, and carbon.-History:Oxaziridine derivatives were first synthesized in the mid 1950s by Emmons and subsequently by Krimm and Horner and Jürgens...
(see Holton Taxol total synthesis
Holton Taxol total synthesis
The Holton Taxol total synthesis, published by Robert A. Holton and his group at Florida State University in 1994 was the first total synthesis of Taxol ....
for another use of this system) and its hydroxyl group together with the ester group were reduced by lithium aluminium hydride
Lithium aluminium hydride
Lithium aluminium hydride, commonly abbreviated to LAH or known as LithAl, is an inorganic compound with the chemical formula LiAlH4. It was discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic synthesis, especially for the reduction of esters,...
to tetrol 14. Finally, the primary alcohol group was protected as a tert-butyldimethylsilyl ether
Silyl ether
Silyl ethers are a group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl group. Silyl ethers are usually used as protecting groups for alcohols in organic synthesis...
by the corresponding silylchloride and 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...
in triol 15.
| Scheme 1 |
|---|
In the second part (Scheme 2) the procedures are still confined to rings A and B. More protective groups were added to triol 15 as reaction with PPTS and 2-methoxypropene gives the acetonide 16. At this point the double bond in ring A was epoxidized with m-CPBA and sodium carbonate
Sodium carbonate
Sodium carbonate , Na2CO3 is a sodium salt of carbonic acid. It most commonly occurs as a crystalline heptahydrate, which readily effloresces to form a white powder, the monohydrate. Sodium carbonate is domestically well-known for its everyday use as a water softener. It can be extracted from the...
to epoxide
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...
17 and a Grob fragmentation
Grob fragmentation
A Grob fragmentation, named for the British chemist Cyril A. Grob, is an elimination reaction taking place when an electrofuge and nucleofuge are situated in positions 1 and 3 on an aliphatic chain...
(also present in the Holton effort) initiated by DABCO
DABCO
DABCO or 1,4-diazabicyclo[2.2.2]octane is a chemical compound. It is a polyurethane and Baylis-Hillman reaction catalyst, complexing ligand and Lewis base. It is used to regulate the reaction rate in Flexplay time-limited DVDs by adjusting pH. Antioxidants, like DABCO, are used to improve the...
opened up the AB ring system in alcohol 18, which was not isolated but protected as a TIPS silyl ether
Silyl ether
Silyl ethers are a group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl group. Silyl ethers are usually used as protecting groups for alcohols in organic synthesis...
19 with triisopropylsilyl triflate and 2,6-lutidine
2,6-Lutidine
2,6-Lutidine is a natural heterocyclic aromatic organic compound. It has been isolated from the basic fraction of coal tar and from bone oil. It is a dimethyl substituted derivative of pyridine. It has been detected in waste water from oil shale processing sites and former creosoting facilities...
. The C1 position was next oxidized by the phosphite ester
Phosphite ester
A phosphite ester or organophosphite is a type of chemical compound with the general structure P3. Phosphite esters can be considered as esters of phosphorous acid, H3PO3. A simple phosphite ester is trimethylphosphite, P3...
, P(OEt)3 and the strong base KOt-Bu, and oxygen to alcohol 20 (the stereochemistry controlled by bowl-shaped AB ring with hydroxylation from unhindered convex direction), the primary alcohol group was deprotected with ammonium chloride
Ammonium chloride
Ammonium chloride NH4Cl is an inorganic compound with the formula NH4Cl. It is a white crystalline salt that is highly soluble in water. Solutions of ammonium chloride are mildly acidic. Sal ammoniac is a name of natural, mineralogical form of ammonium chloride...
in methanol
Methanol
Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...
to diol
Diol
A diol or glycol is a chemical compound containing two hydroxyl groups A geminal diol has two hydroxyl groups bonded to the same atom...
21 and two reductions first with NaBH4
Sodium borohydride
Sodium borohydride, also known as sodium tetrahydridoborate, is an inorganic compound with the formula NaBH4. This white solid, usually encountered as a powder, is a versatile reducing agent that finds wide application in chemistry, both in the laboratory and on a technical scale. Large amounts are...
to triol 22 and then hydrogen gas
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
and Crabtree's catalyst
Crabtree's catalyst
Crabtree's catalyst is the name given to a complex of iridium with 1,5-cyclooctadiene, tris-cyclohexylphosphine, and pyridine. It is a homogeneous catalyst for hydrogenation reactions, developed by Robert H. Crabtree, a professor at Yale University...
give triol 23. These positions were protected by trimethylsilyl chloride
Trimethylsilyl chloride
Trimethylsilyl chloride, also known as chlorotrimethylsilane is a silyl halide, with a variety of different uses in chemistry. It has the formula 3SiCl, and under standard conditions it is a colourless liquid, which is stable in the absence of water...
and pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
to 24 and then triphosgene
Triphosgene
Triphosgene is a chemical compound that is used as a safer substitute for phosgene, because at room temperature it is a solid crystal, as opposed to phosgene which is a gas. Triphosgene crystals decompose at around 130 °C, although, the decomposition temperature of impure samples can be much lower...
to 25 in order to facilitate the oxidation of the primary alcohol group to the aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
26 by PCC
Pyridinium chlorochromate
Pyridinium chlorochromate is a reddish orange solid reagent used to oxidize primary alcohols to aldehydes and secondary alcohols to ketones. Pyridinium chlorochromate, or PCC, will not fully oxidize a primary alcohol to the carboxylic acid as does the Jones reagent. A disadvantage to using PCC is...
.
| Scheme 2 |
|---|
C Ring synthesis
The next part constructed the C ring starting from aldehyde 26, which was extended by one carbon atom to homologueHomologous series
In chemistry, a homologous series is a series of compounds with a similar general formula, possessing similar chemical properties due to the presence of the same functional group, and showing a gradation in physical properties as a result of increase in molecular size and mass...
27 in a Wittig reaction
Wittig reaction
The Wittig reaction is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide to give an alkene and triphenylphosphine oxide....
with Methoxymethylenetriphenylphosphine
Methoxymethylenetriphenylphosphine
Methoxymethylenetriphenylphosphine is a Wittig reagent with used as an reagent in the homologization of aldehydes and ketones to extended aldehydes, an organic reaction first reported in 1958 ....
(Scheme 3). The acetonide group was removed by dilute hydrochloric acid
Hydrochloric acid
Hydrochloric acid is a solution of hydrogen chloride in water, that is a highly corrosive, strong mineral acid with many industrial uses. It is found naturally in gastric acid....
and sodium iodide
Sodium iodide
Sodium iodide is a white, crystalline salt with chemical formula NaI used in radiation detection, treatment of iodine deficiency, and as a reactant in the Finkelstein reaction.-Uses:Sodium iodide is commonly used to treat and prevent iodine deficiency....
in dioxane and one hydroxyl group in the resulting diol 28 was protected as the triethylsilyl ether (TES) 29 with the corresponding silyl chloride and pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
enabling oxidation of the remaining hydroxyl group to the ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
30 with the Dess-Martin periodinane
Dess-Martin periodinane
Dess–Martin periodinane is a chemical reagent used to oxidize primary alcohols to aldehydes and secondary alcohols to ketones. This periodinane has several advantages over chromium- and DMSO-based oxidants that include milder conditions , shorter reaction times, higher yields, simplified workups,...
. Reaction with Eschenmoser's salt
Eschenmoser's salt
Eschenmoser's salt, dimethylmethylideneammonium iodide, is a strong dimethylaminomethylating agent, used to prepare derivatives of the type RCH2N2. Enolates, enolsilylethers, and even more acidic ketones undergo efficient dimethylaminomethylation...
placed a methylene
Methylene
Methylene is a chemical species in which a carbon atom is bonded to two hydrogen atoms. Three different possibilities present themselves:* the -CH2- substituent group: e.g., dichloromethane ....
group (C20 in the Taxol framework) in the alpha position of the aldehyde to 31 and the next reaction introduced (the still lacking) C6 and C7 as the Grignard reagent of allyl bromide
Allyl bromide
Allyl bromide is an organic halide. Its refractive index is 1.4697 . Allyl bromide is an alkylating agent used in synthesis of polymers, pharmaceuticals, allyls and other organic compounds. Physically, allyl bromide is a clear liquid with an intense, acrid, and persistent smell...
in a nucleophilic addition
Nucleophilic addition
In organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....
aided by zinc(II) chloride, which blocked the Grignard from attack on carbonate group, to alcohol 32. The newly formed alcohol was protected as the BOM ether 33 with BOMCl and N,N-diisopropylethylamine. After removal of the TES protecting group with ammonium fluoride
Ammonium fluoride
Ammonium fluoride is the inorganic compound with the formula NH4F. It crystallizes as small colourless prisms, having a sharp saline taste, and is exceedingly soluble in water.-Crystal structure:...
, the carbonate
Carbonate ester
A carbonate ester is a functional group in organic chemistry consisting of a carbonyl group flanked by two alkoxy groups. The general structure of these carbonates is R1OOR2 and they are related to esters R1OR and ethers R1OR2 and also to the inorganic carbonates.Carbonate esters are used as...
group in 34 was converted to a hydroxybenzoate group by action of phenyllithium
Phenyllithium
Phenyllithium is an organometallic agent with the empirical formula C6H5Li. It is most commonly used as a metalating agent in organic syntheses and a substitute for Grignard reagents for introducing phenyl groups in organic syntheses...
and the secondary alcohol to the acetate
Acetate
An acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...
35 by in situ
In situ
In situ is a Latin phrase which translated literally as 'In position'. It is used in many different contexts.-Aerospace:In the aerospace industry, equipment on board aircraft must be tested in situ, or in place, to confirm everything functions properly as a system. Individually, each piece may...
reaction with acetic anhydride
Acetic anhydride
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...
and DMAP. In the next step the acyloin
Acyloin
Acyloins are a class of organic compounds in organic chemistry sharing a common functional group consisting of a hydroxyl group placed on the α-position of a carbonyl group.- Nomenclature :Common types of ketols include:...
group had its positions swapped by reaction with triazabicyclodecene
Triazabicyclodecene
Triazabicyclodecene is a commercially available bicyclic strong guanidine base...
(other amine bases fail) forming 36 and in the final steps ring closure of ring C was accomplished by ozonolysis
Ozonolysis
Ozonolysis is the cleavage of an alkene or alkyne with ozone to form organic compounds in which the multiple carbon–carbon bond has been replaced by a double bond to oxygen...
at the allyl group to 37 and Aldol reaction
Aldol reaction
The aldol reaction is a powerful means of forming carbon–carbon bonds in organic chemistry.Discovered independently by Charles-Adolphe Wurtz and Alexander Porfyrevich Borodin in 1872, the reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound...
with 4-pyrrolidinopyridine to 38.
| Scheme 3 |
|---|
D Ring synthesis
The final part dealt with the construction of oxetaneOxetane
Oxetane, or 1,3-propylene oxide, is an heterocyclic organic compound with the molecular formula C3H6O, having a four-membered ring with three carbon atoms and one oxygen atom....
ring D starting with protection of the alcohol group in 38 (Scheme 4). as a TROC alcohol 39 with 2,2,2-trichloroethyl chloroformate and pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
. The OBOM group was replaced by a bromine
Bromine
Bromine ") is a chemical element with the symbol Br, an atomic number of 35, and an atomic mass of 79.904. It is in the halogen element group. The element was isolated independently by two chemists, Carl Jacob Löwig and Antoine Jerome Balard, in 1825–1826...
group in three steps: deprotection to 40 with hydrochloric acid
Hydrochloric acid
Hydrochloric acid is a solution of hydrogen chloride in water, that is a highly corrosive, strong mineral acid with many industrial uses. It is found naturally in gastric acid....
and sodium iodide
Sodium iodide
Sodium iodide is a white, crystalline salt with chemical formula NaI used in radiation detection, treatment of iodine deficiency, and as a reactant in the Finkelstein reaction.-Uses:Sodium iodide is commonly used to treat and prevent iodine deficiency....
, mesylation to 41 with mesyl chloride, DMAP and pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
and nucleophilic substitution
Nucleophilic substitution
In organic and inorganic chemistry, nucleophilic substitution is a fundamental class of reactions in which an electron nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms called the leaving group; the positive or partially positive...
with inversion of configuration with lithium bromide
Lithium bromide
Lithium bromide, or LiBr, is a chemical compound of lithium and bromine. Its extreme hygroscopic character makes LiBr useful as a desiccant in certain air conditioning systems.-Production and properties:...
to bromide 42. Because the oxidation of the alkene
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...
group to the diol
Diol
A diol or glycol is a chemical compound containing two hydroxyl groups A geminal diol has two hydroxyl groups bonded to the same atom...
43 with osmium tetroxide was accompanied by the undesired migration of the benzoate group, this step was taken to completion with 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...
as 44. Two additional countermeasures were required: reprotection of the diol as the carbonate ester
Carbonate ester
A carbonate ester is a functional group in organic chemistry consisting of a carbonyl group flanked by two alkoxy groups. The general structure of these carbonates is R1OOR2 and they are related to esters R1OR and ethers R1OR2 and also to the inorganic carbonates.Carbonate esters are used as...
45 with triphosgene
Triphosgene
Triphosgene is a chemical compound that is used as a safer substitute for phosgene, because at room temperature it is a solid crystal, as opposed to phosgene which is a gas. Triphosgene crystals decompose at around 130 °C, although, the decomposition temperature of impure samples can be much lower...
and removal of the benzoate group (KCN) to alcohol 46 in preparation of the actual ring closure to the oxetane 47 with N,N-diisopropylethylamine. In the final steps the tertiary alcohol was acylated in 48, the TIPS group removed in 49 and the benzoate group re-introduced in 50.
Tail addition of the Ojima lactam
Ojima lactam
The Ojima lactam is an organic compound of some importance in the commercial production of Taxol. This lactam was first synthesized by Iwao Ojima . The organic synthesis is an illustration of asymmetric synthesis via a chiral auxiliary....
51 was not disclosed in detail but finally taxol 52 was formed in several steps similar to the other efforts.
| Scheme 4 |
|---|
External links
- Wender Taxol Synthesis @ SynArchive.com
- The Wender Taxol Mug: Link
See also
- Paclitaxel total synthesis
- Danishefsky Taxol total synthesisDanishefsky Taxol total synthesisThe Danishefsky Taxol total synthesis in organic chemistry is an important third Taxol synthesis published by the group of Samuel Danishefsky in 1996...
- Holton Taxol total synthesisHolton Taxol total synthesisThe Holton Taxol total synthesis, published by Robert A. Holton and his group at Florida State University in 1994 was the first total synthesis of Taxol ....
- Kuwajima Taxol total synthesisKuwajima Taxol total synthesisThe Kuwajima Taxol total synthesis by the group of Isao Kuwajima of the Tokyo Institute of Technology is one of several efforts in taxol total synthesis published in the 1990s...
- Mukaiyama Taxol total synthesisMukaiyama Taxol total synthesisThe Mukaiyama taxol total synthesis published by the group of Teruaki Mukaiyama of the Tokyo University of Science between 1997 and 1999 was the 6th successful taxol total synthesis. The total synthesis of Taxol is considered a hallmark in organic synthesis....
- Nicolaou Taxol total synthesisNicolaou Taxol total synthesisThe Nicolaou Taxol total synthesis, published by K. C. Nicolaou and his group in 1994 concerns the total synthesis of Taxol. This organic synthesis was included in Nicolaou's book, 'Classics in Total Synthesis'....