Kuwajima Taxol total synthesis
Encyclopedia
The 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. The total synthesis
of Taxol is considered a landmark in organic synthesis
.
This synthesis is truly synthetic without any help from small biomolecule precursors and also a linear synthesis with molecule ring construction in the order of A, B, C, D. At some point chirality
is locked into the molecule via an asymmetric synthesis step which is unique compared to the other efforts. In common with the other efforts the tail addition is based on the Ojima lactam
.
The 20 carbon frame is constructed from several pieces: propargyl alcohol
(C1, C2, C14), propionaldehyde
(C13, C12, C18), isobutyric acid
(C15, C16, C17, C11), Trimethyl(phenylthiomethyl)silane (C10), 2-bromobenzaldehyde (C3 to C9), diethylaluminum cyanide (C19) and trimethylsilylmethyl bromide (C20)
protected propargyl alcohol
1.1 (the C2-C1-C14 fragment) and propionaldehyde
1.2 (fragment C13-C12-C18) in a nucleophilic addition
with n-butyllithium
to alcohol
1.3. The Lindlar catalyst
then reduced the alkyne
to the alkene
in 1.4 and Swern oxidation
convered the alcohol group to the enone
group in 1.5. Fragment C11-C15-C16-C17 1.6 was then added as the lithium enol
ate of isobutyric acid
ethyl ester
in a conjugate addition to gamma keto ester 1.7. A Claisen condensation
closed the ring to 1.8 and the intermediate enol is captured by pivaloyl chloride
(piv) as a protective group. The THP group was removed with TsOH to 1.9 and the formed alcohol
oxidized by Swern oxidation
to aldehyde
1.10. The TIPS silyl enol ether
1.11 was formed by reaction with the triflate
TIPSOtf and DBU
in DMAP setting the stage for asymmetric dihydroxylation to hydroxyaldehyde 1.12. The piv protecting group was then replaced by a TIPS group in 1.14 after protecting the aldehyde as the aminal
1.13 and as this group is automatically lost on column chromatography
, the step was repeated to aminal 1.15. The C10 fragment was then introduced by the lithium salt of Trimethyl(phenylthiomethyl)silane 1.16 in a Peterson olefination
to the sulfide
1.17 followed by deprotection to completed ring A 1.18. The A ring is now complete with the aldehyde group and de sulfide group in place for anchoring with ring C forming ring B.
to the aldehyde of 2.1 (scheme 2) with dibenzyl
acetal
of 2-bromobenzaldehyde 2.2 as its aryllithium
. This step is much in common with the B ring synthesis in the Nicolaou Taxol total synthesis
except that the aldehyde group is located at ring A and not ring B. The diol
in 2.3 was protected as the boronic ester 2.4 preparing the molecule for upper part ring closure with tin tetrachloride to tricycle 2.5 in a Grob fragmentation
-like reaction.
After deprotection (pinacol
) to diol 2.6, DIBAL reduction to triol 2.7 and TBS reprotection (TBSOtf, lutidine) to alcohol 2.8 it was possible to remove the phenylsulfide group in a with tributyltin hydride
and AIBN(see Barton-McCombie deoxygenation
) to alcohol 2.9. Palladium on carbon
hydrogenation
removed the benzyl protecting group allowing the Swern oxidation
of 2.10 to ketone 2.11
(potassium
, ammonia
, tetrahydrofuran
, -78°C, then ethanol
) to diene
3.2. Deprotection (TBAF) to diol 3.3, reprotection as the benzaldehyde
acetal
3.4 and reduction (sodium borohydride
) to alcohol 3.5 allowed the oxidation of the diene to the 1,4-butenediol 3.6. In this photochemical [4+2]cycloaddition
, singlet oxygen
was generated from oxygen and rose bengal
and the intermediate peroxide
was reduced with thiourea
. The next order of business was introduction of the C19 fragment: the new diol group was protected as the PMP acetal
3.7 (PMP stands for p-methoxyphenyl) allowing the oxidation of the C4 alcohol to ketone 3.8 with the Dess-Martin periodinane
. Diethylaluminum cyanide reacted in a conjugate addition to the enone group to nitrile
3.9. The enol was protected as the TBS ether
3.10 allowing for the reduction of the nitrile group first to the aldehyde
with DIBAL and then on to the alcohol
3.11 with Lithium aluminium hydride
. The alcohol group was replaced by bromine in a Appel reaction
which caused an elimination reaction
(loss of HBr) to cyclopropane
3.12. Treatment with hydrochloric acid
formed ketone 3.13, reaction with Samarium(II) iodide
gave ring-opening finally putting the C19 methyl group in place in 3.14 and deprotection (TBAF) and enol-ketone conversion gave hydroxyketone 3.15
, sodium bicarbonate
) again in 4.4 it was possible to oxidize the C19 alcohol to the ketone 4.5 with Dess-Martin periodinane
. In a new round of protections the C7 alcohol was converted to the 2-methoxy-2-propyl (MOP) ether 4.6 with 2-propenylmethylether and PPTS
and the C7 ketone was converted to its enolate 4.7 by reaction with KHMDS
and N,N-bis(trifluoromethylsulfonyl)aniline. These preambles facilitated the introduction of the final missing C20 fragment as the Grignard reagent trimethylsilylmethylmagnesium bromide which coupled
with the triflate in a tetrakis(triphenylphosphine)palladium(0)
catalysed reaction to the silane
4.8. The trimethylsilyl
group eliminated on addition of NCS
to organochloride
4.9. Prior to ring-closing the D ring there was some unfinished business in ring C. A C10 alcohol was introduced by MoOPH oxidation to 4.10 but with the wrong stereochemistry
. After acetylation
to 4.11 and inversion of configuration with added base DBN this problem was remedied in compound 4.12. Next dihydroxylation with Osmium(VIII) oxide
formed the diol
4.13 with the primary alcohol on addition of base DBU
displacing the chlorine atom in a nucleophilic aliphatic substitution to oxetane
4.14.
5.1 (scheme 5) the MOM protecting group is removed in 5.2 (PPTS
) and replaced by a TES group TESCl) in 5.3. The acetal
group was removed in 5.4 (hydrogenation
PdOH2, H2) and replaced by a carbonate ester
group in 5.5 (triphosgene
, pyridine
). The tertiary alcohol group was acetylated
in 5.6 and in the final step the carbonate group was opened by reaction with phenyllithium
to the hydroxyester 5.7.
Prior to tail addition the TES protective group was removed in 5.8 (hydrogen fluoride
pyridine
) and replaced by a TROC (trichloroethyl carbonate, TROCCl ) group in 5.9. The C13 alcohol protective group was removed in 5.10 (TASF) enabling the tail addition of Ojima lactam
5.11 (this step is common with all total synthetic efforts to date) to 5.12 with Lithium bis(trimethylsilyl)amide
. The synthesis was completed with TROC removal (zinc
, acetic acid
) to taxol 5.13.
Tokyo Institute of Technology
The Tokyo Institute of Technology is a public research university located in Greater Tokyo Area, Japan. Tokyo Tech is the largest institution for higher education in Japan dedicated to science and technology. Tokyo Tech enrolled 4,850 undergaraduates and 5006 graduate students for 2009-2010...
is one of several efforts in 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...
published in the 1990s. The total synthesis
Total synthesis
In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...
of Taxol is considered a landmark in organic synthesis
Organic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...
.
This synthesis is truly synthetic without any help from small biomolecule precursors and also a linear synthesis with molecule ring construction in the order of A, B, C, D. At some point chirality
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....
is locked into the molecule via an asymmetric synthesis step which is unique compared to the other efforts. In common with the other efforts the tail addition is based on 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....
.
The 20 carbon frame is constructed from several pieces: propargyl alcohol
Propargyl alcohol
Propargyl alcohol, or 2-propyn-1-ol, is an organic compound which is a simple alcohol containing an alkyne functional group . Propargyl alcohol is a clear colorless viscous liquid that is miscible with water and most polar organic solvents. It is insoluble in most hydrocarbon solvents...
(C1, C2, C14), propionaldehyde
Propionaldehyde
Propionaldehyde or propanal is the organic compound with the formula CH3CH2CHO. It is a saturated 3-carbon aldehyde and is a structural isomer of acetone...
(C13, C12, C18), isobutyric acid
Isobutyric acid
Isobutyric acid, also known as 2-methylpropanoic acid, is a carboxylic acid with structural formula 2-CH-COOH. It is found in the free state in carobs and in the root of Arnica dulcis, and as an ethyl ester in croton oil....
(C15, C16, C17, C11), Trimethyl(phenylthiomethyl)silane (C10), 2-bromobenzaldehyde (C3 to C9), diethylaluminum cyanide (C19) and trimethylsilylmethyl bromide (C20)
Synthesis A ring
Ring A synthesis (scheme 1) started by joining the THPTetrahydropyran
Tetrahydropyran is the organic compound consisting of a saturated six-membered ring containing five carbon atoms and one oxygen atom. The compound is a colourless volatile liquid, but is obscure. Derivatives of tetrahydropyran are, however, more common. Tetrahydropyranyl ethers derived from the...
protected propargyl alcohol
Propargyl alcohol
Propargyl alcohol, or 2-propyn-1-ol, is an organic compound which is a simple alcohol containing an alkyne functional group . Propargyl alcohol is a clear colorless viscous liquid that is miscible with water and most polar organic solvents. It is insoluble in most hydrocarbon solvents...
1.1 (the C2-C1-C14 fragment) and propionaldehyde
Propionaldehyde
Propionaldehyde or propanal is the organic compound with the formula CH3CH2CHO. It is a saturated 3-carbon aldehyde and is a structural isomer of acetone...
1.2 (fragment C13-C12-C18) 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....
with n-butyllithium
N-Butyllithium
n-Butyllithium is an organolithium reagent. It is widely used as a polymerization initiator in the production of elastomers such as polybutadiene or styrene-butadiene-styrene...
to 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....
1.3. The Lindlar catalyst
Lindlar catalyst
A Lindlar catalyst is a heterogeneous catalyst that consists of palladium deposited on calcium carbonate and treated with various forms of lead. The lead additive serves to deactivate the palladium sites. A variety of "catalyst poisons" have been used including lead acetate and lead oxide. The...
then reduced 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...
to 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...
in 1.4 and Swern oxidation
Swern oxidation
The Swern oxidation, named after Daniel Swern, is a chemical reaction whereby a primary or secondary alcohol is oxidized to an aldehyde or ketone using oxalyl chloride, dimethyl sulfoxide and an organic base, such as triethylamine...
convered the alcohol group to the 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....
group in 1.5. Fragment C11-C15-C16-C17 1.6 was then added as the lithium enol
Enol
Enols are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Alkenes with a hydroxyl group on both sides of the double bond are called enediols. Deprotonated anions of enols are called enolates...
ate of isobutyric acid
Isobutyric acid
Isobutyric acid, also known as 2-methylpropanoic acid, is a carboxylic acid with structural formula 2-CH-COOH. It is found in the free state in carobs and in the root of Arnica dulcis, and as an ethyl ester in croton oil....
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...
in a conjugate addition to gamma keto ester 1.7. A Claisen condensation
Claisen condensation
The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone...
closed the ring to 1.8 and the intermediate enol is captured by pivaloyl chloride
Pivalic acid
Pivalic acid is a carboxylic acid with a molecular formula of 3CCO2H. This colourless, odiferous organic compound is solid at room temperature.-Industrial route:...
(piv) as a protective group. The THP group was removed with TsOH to 1.9 and the formed 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....
oxidized by Swern oxidation
Swern oxidation
The Swern oxidation, named after Daniel Swern, is a chemical reaction whereby a primary or secondary alcohol is oxidized to an aldehyde or ketone using oxalyl chloride, dimethyl sulfoxide and an organic base, such as triethylamine...
to 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....
1.10. The TIPS silyl enol ether
Silyl enol ether
Silyl enol ethers in organic chemistry are a class of organic compounds that share a common functional group composed of an enolate bonded through its oxygen terminus to an organosilicon group....
1.11 was formed by reaction with the triflate
Triflate
Trifluoromethanesulfonate, also known by the trivial name triflate, is a functional group with the formula CF3SO3-. The triflate group is often represented by -OTf, as opposed to -Tf...
TIPSOtf and DBU
DBU (chemistry)
1,8-Diazabicyclo[5.4.0]undec-7-ene, or more commonly DBU, is a chemical compound and belongs to the class of amidine compounds. It is used in organic synthesis as a catalyst and complexing ligand and a strong non-nucleophilic base.It is used as a curing agent for epoxy; it is used as a protecting...
in DMAP setting the stage for asymmetric dihydroxylation to hydroxyaldehyde 1.12. The piv protecting group was then replaced by a TIPS group in 1.14 after protecting the aldehyde as the aminal
Aminal
An aminal or aminoacetal is a functional group or type of chemical compound that has two amine groups attached to the same carbon atom: -C-. Again R can be hydrogen or an alkyl group....
1.13 and as this group is automatically lost on column chromatography
Column chromatography
Column chromatography in chemistry is a method used to purify individual chemical compounds from mixtures of compounds. It is often used for preparative applications on scales from micrograms up to kilograms.The main advantage of column chromatography is the relatively low cost and disposability...
, the step was repeated to aminal 1.15. The C10 fragment was then introduced by the lithium salt of Trimethyl(phenylthiomethyl)silane 1.16 in a Peterson olefination
Peterson olefination
The Peterson olefination is the chemical reaction of α-silyl carbanions 1 with ketones to form a β-hydroxysilane 2 which eliminates to form alkenes 3.Several reviews have been published....
to the sulfide
Sulfide
A sulfide is an anion of sulfur in its lowest oxidation state of 2-. Sulfide is also a slightly archaic term for thioethers, a common type of organosulfur compound that are well known for their bad odors.- Properties :...
1.17 followed by deprotection to completed ring A 1.18. The A ring is now complete with the aldehyde group and de sulfide group in place for anchoring with ring C forming ring B.
| Scheme 1 |
|---|
Synthesis B ring
The bottom part of ring B was constructed by nucleophilic additionNucleophilic 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 aldehyde of 2.1 (scheme 2) with dibenzyl
Benzyl
In organic chemistry, benzyl is the term used to describe the substituent or molecular fragment possessing the structure C6H5CH2-. Benzyl features a benzene ring attached to a CH2 group.-Nomenclature:...
acetal
Acetal
An acetal is a molecule with two single-bonded oxygen atoms attached to the same carbon atom.Traditional usages distinguish ketals from acetals...
of 2-bromobenzaldehyde 2.2 as its aryllithium
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...
. This step is much in common with the B ring synthesis in the Nicolaou Taxol total synthesis
Nicolaou Taxol total synthesis
The 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'....
except that the aldehyde group is located at ring A and not ring B. 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...
in 2.3 was protected as the boronic ester 2.4 preparing the molecule for upper part ring closure with tin tetrachloride to tricycle 2.5 in 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...
-like reaction.
After deprotection (pinacol
Pinacol
Pinacol is a white solid organic compound.-Preparation:It may be produced by the pinacol coupling reaction from acetone:-Reactions:As a vicinal-diol, it can rearrange to pinacolone by the pinacol rearrangement, e.g...
) to diol 2.6, DIBAL reduction to triol 2.7 and TBS reprotection (TBSOtf, lutidine) to alcohol 2.8 it was possible to remove the phenylsulfide group in a with tributyltin hydride
Tributyltin hydride
Tributyltin hydride is an organotin compound with the formula 3SnH. It is a colorless liquid that is soluble in organic solvents. The compound is used as a source of hydrogen atoms in organic synthesis.-Synthesis and characterization:...
and AIBN(see Barton-McCombie deoxygenation
Barton-McCombie deoxygenation
The Barton–McCombie deoxygenation is an organic reaction in which an hydroxy functional group in an organic compound is replaced by a hydride to give an alkyl group . It is named for the British chemists Sir Derek Harold Richard Barton and Stuart W. McCombie.This deoxygenation reaction is a...
) to alcohol 2.9. Palladium on carbon
Palladium on carbon
Palladium on carbon, often referred to as Pd/C, is a form of palladium used for catalysis. It is usually used for catalytic hydrogenations in organic chemistry...
hydrogenation
Hydrogenation
Hydrogenation, to treat with hydrogen, also a form of chemical reduction, is a chemical reaction between molecular hydrogen and another compound or element, usually in the presence of a catalyst. The process is commonly employed to reduce or saturate organic compounds. Hydrogenation typically...
removed the benzyl protecting group allowing the Swern oxidation
Swern oxidation
The Swern oxidation, named after Daniel Swern, is a chemical reaction whereby a primary or secondary alcohol is oxidized to an aldehyde or ketone using oxalyl chloride, dimethyl sulfoxide and an organic base, such as triethylamine...
of 2.10 to ketone 2.11
| Scheme 2 |
|---|
Synthesis C ring
Completion of the C ring required complete reduction of the arene, placement of para oxygen atoms and importantly introduction of the C19 methyl group. The first assault on the aromatic ring in 3.1 (scheme 3) was launched with Birch reductionBirch reduction
The Birch Reduction is an organic reaction which is particularly useful in synthetic organic chemistry. The reaction was reported in 1944 by the Australian chemist Arthur Birch working in the Dyson Perrins Laboratory in the University of Oxford, building on earlier work by Wooster and Godfrey in...
(potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
, ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
, tetrahydrofuran
Tetrahydrofuran
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...
, -78°C, then ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
) to 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...
3.2. Deprotection (TBAF) to diol 3.3, reprotection as the benzaldehyde
Benzaldehyde
Benzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...
acetal
Acetal
An acetal is a molecule with two single-bonded oxygen atoms attached to the same carbon atom.Traditional usages distinguish ketals from acetals...
3.4 and reduction (sodium borohydride
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 alcohol 3.5 allowed the oxidation of the diene to the 1,4-butenediol 3.6. In this photochemical [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...
, singlet oxygen
Singlet oxygen
Singlet oxygen is the common name used for the diamagnetic form of molecular oxygen , which is less stable than the normal triplet oxygen. Because of its unusual properties, singlet oxygen can persist for over an hour at room temperature, depending on the environment...
was generated from oxygen and rose bengal
Rose bengal
Rose Bengal is a stain. Its sodium salt is commonly used in eye drops to stain damaged conjunctival and corneal cells and thereby identify damage to the eye...
and the intermediate 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·...
was reduced with thiourea
Thiourea
Thiourea is an organosulfur compound of with the formula SC2 . It is structurally similar to urea, except that the oxygen atom is replaced by a sulfur atom, but the properties of urea and thiourea differ significantly. Thiourea is a reagent in organic synthesis. "Thioureas" refers to a broad...
. The next order of business was introduction of the C19 fragment: the new diol group was protected as the PMP acetal
Acetal
An acetal is a molecule with two single-bonded oxygen atoms attached to the same carbon atom.Traditional usages distinguish ketals from acetals...
3.7 (PMP stands for p-methoxyphenyl) allowing the oxidation of the C4 alcohol to ketone 3.8 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,...
. Diethylaluminum cyanide reacted in a conjugate addition to the enone group to nitrile
Nitrile
A nitrile is any organic compound that has a -C≡N functional group. The prefix cyano- is used interchangeably with the term nitrile in industrial literature. Nitriles are found in many useful compounds, one example being super glue .Inorganic compounds containing the -C≡N group are not called...
3.9. The enol was protected as the TBS 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...
3.10 allowing for the reduction of the nitrile group first 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....
with DIBAL and then on 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....
3.11 with 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,...
. The alcohol group was replaced by bromine in a Appel reaction
Appel reaction
The Appel reaction is an organic reaction that converts an alcohol into an alkyl chloride using triphenylphosphine and carbon tetrachloride. The use of carbon tetrabromide or bromine as a halide source will yield alkyl bromides, whereas using methyl iodide or iodine gives alkyl iodides...
which caused an elimination reaction
Elimination reaction
An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism...
(loss of HBr) to cyclopropane
Cyclopropane
Cyclopropane is a cycloalkane molecule with the molecular formula C3H6, consisting of three carbon atoms linked to each other to form a ring, with each carbon atom bearing two hydrogen atoms...
3.12. Treatment 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....
formed ketone 3.13, reaction with Samarium(II) iodide
Samarium(II) iodide
Samarium iodide is a green solid composed of samarium and iodine, with a melting point of 520 °C where the samarium atom has a coordination number of seven in a capped octahedral configuration...
gave ring-opening finally putting the C19 methyl group in place in 3.14 and deprotection (TBAF) and enol-ketone conversion gave hydroxyketone 3.15
| Scheme 3 |
|---|
Synthesis D ring
By protecting the diol group in triol 4.1 (scheme 4) as the phenyl boronic ester 4.2, the remaining alcohol group could be protected as the TBS ether 4.3. After deprotecting the diol group (hydrogen peroxideHydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...
, sodium bicarbonate
Sodium bicarbonate
Sodium bicarbonate or sodium hydrogen carbonate is the chemical compound with the formula Na HCO3. Sodium bicarbonate is a white solid that is crystalline but often appears as a fine powder. It has a slightly salty, alkaline taste resembling that of washing soda . The natural mineral form is...
) again in 4.4 it was possible to oxidize the C19 alcohol to the ketone 4.5 with 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,...
. In a new round of protections the C7 alcohol was converted to the 2-methoxy-2-propyl (MOP) ether 4.6 with 2-propenylmethylether and PPTS
Pyridinium p-toluenesulfonate
Pyridinium p-toluenesulfonate is a salt of pyridine and p-toluenesulfonic acid. It is often called PPTS. It appears a colourless solid.Masaki Miyashita studied this compound and found it efficient to deprotect tetrahydropyranyl group ....
and the C7 ketone was converted to its enolate 4.7 by reaction with KHMDS
Potassium bis(trimethylsilyl)amide
Potassium bisamide is the chemical compound with the formula 2NK...
and N,N-bis(trifluoromethylsulfonyl)aniline. These preambles facilitated the introduction of the final missing C20 fragment as the Grignard reagent trimethylsilylmethylmagnesium bromide which coupled
Coupling reaction
A coupling reaction in organic chemistry is a catch-all term for a variety of reactions where two hydrocarbon fragments are coupled with the aid of a metal catalyst...
with the triflate in a tetrakis(triphenylphosphine)palladium(0)
Tetrakis(triphenylphosphine)palladium(0)
Tetrakispalladium is the chemical compound Pd[P3]4, often abbreviated Pd4, or even PdP4. It is a bright yellow crystalline solid that becomes brown upon decomposition in air.-Structure and properties:...
catalysed reaction to the silane
Silane
Silane is a toxic, extremely flammable chemical compound with chemical formula SiH4. In 1857, the German chemists and Friedrich Woehler discovered silane among the products formed by the action of hydrochloric acid on aluminum silicide, which they had previously prepared...
4.8. The trimethylsilyl
Trimethylsilyl
A trimethylsilyl group is a functional group in organic chemistry. This group consists of three methyl groups bonded to a silicon atom [−Si3], which is in turn bonded to the rest of a molecule...
group eliminated on addition of NCS
N-Bromosuccinimide
N-Bromosuccinimide or NBS is a chemical reagent which is used in radical substitution and electrophilic addition reactions in organic chemistry. NBS can be considered a convenient source of cationic bromine.-Preparation:...
to organochloride
Organochloride
An organochloride, organochlorine, chlorocarbon, chlorinated hydrocarbon, or chlorinated solvent is an organic compound containing at least one covalently bonded chlorine atom. Their wide structural variety and divergent chemical properties lead to a broad range of applications...
4.9. Prior to ring-closing the D ring there was some unfinished business in ring C. A C10 alcohol was introduced by MoOPH oxidation to 4.10 but with the wrong stereochemistry
Stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
. After acetylation
Acetylation
Acetylation describes a reaction that introduces an acetyl functional group into a chemical compound...
to 4.11 and inversion of configuration with added base DBN this problem was remedied in compound 4.12. Next dihydroxylation with Osmium(VIII) oxide
Osmium(VIII) oxide
Osmium tetroxide is the chemical compound with the formula OsO4. The compound is noteworthy for its many uses, despite the rarity of osmium...
formed 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...
4.13 with the primary alcohol on addition of base DBU
DBU (chemistry)
1,8-Diazabicyclo[5.4.0]undec-7-ene, or more commonly DBU, is a chemical compound and belongs to the class of amidine compounds. It is used in organic synthesis as a catalyst and complexing ligand and a strong non-nucleophilic base.It is used as a curing agent for epoxy; it is used as a protecting...
displacing the chlorine atom in a nucleophilic aliphatic substitution to oxetane
Oxetane
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....
4.14.
| Scheme 4 |
|---|
Tail addition
The C1, C2 and C4 functional groups were put in place next and starting from 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....
5.1 (scheme 5) the MOM protecting group is removed in 5.2 (PPTS
Pyridinium p-toluenesulfonate
Pyridinium p-toluenesulfonate is a salt of pyridine and p-toluenesulfonic acid. It is often called PPTS. It appears a colourless solid.Masaki Miyashita studied this compound and found it efficient to deprotect tetrahydropyranyl group ....
) and replaced by a TES group TESCl) in 5.3. The acetal
Acetal
An acetal is a molecule with two single-bonded oxygen atoms attached to the same carbon atom.Traditional usages distinguish ketals from acetals...
group was removed in 5.4 (hydrogenation
Hydrogenation
Hydrogenation, to treat with hydrogen, also a form of chemical reduction, is a chemical reaction between molecular hydrogen and another compound or element, usually in the presence of a catalyst. The process is commonly employed to reduce or saturate organic compounds. Hydrogenation typically...
PdOH2, H2) and replaced by a 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...
group in 5.5 (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...
, 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 tertiary alcohol group was acetylated
Acetylation
Acetylation describes a reaction that introduces an acetyl functional group into a chemical compound...
in 5.6 and in the final step the carbonate group was opened by reaction with 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...
to the hydroxyester 5.7.
Prior to tail addition the TES protective group was removed in 5.8 (hydrogen fluoride
Hydrogen fluoride
Hydrogen fluoride is a chemical compound with the formula HF. This colorless gas is the principal industrial source of fluorine, often in the aqueous form as hydrofluoric acid, and thus is the precursor to many important compounds including pharmaceuticals and polymers . HF is widely used in the...
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 replaced by a TROC (trichloroethyl carbonate, TROCCl ) group in 5.9. The C13 alcohol protective group was removed in 5.10 (TASF) enabling the tail addition of 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....
5.11 (this step is common with all total synthetic efforts to date) to 5.12 with Lithium bis(trimethylsilyl)amide
Lithium bis(trimethylsilyl)amide
Lithium bisamide is the organosilicon compound with the formula [3Si]2NLi. This colourless solid is a strong non-nucleophilic base used for deprotonation reactions and as a ligand...
. The synthesis was completed with TROC removal (zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
, 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 taxol 5.13.
| Scheme 5 |
|---|
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 ....
- 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'....
- Wender Taxol total synthesisWender Taxol total synthesisThe Wender Taxol total synthesis in organic chemistry describes a Taxol total synthesis 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...