Holton Taxol total synthesis
Encyclopedia
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 (generic name: paclitaxel).
The Holton Taxol total synthesis
is a good example of a linear synthesis starting from commercially available natural compound patchoulene oxide.
This epoxide
can be obtained in two steps from the terpene patchoulol
and also from borneol
. The reaction sequence is also enantioselective, synthesizing (+)-Taxol from (-)-patchoulene oxide or (-)-Taxol from (-)-borneol with a reported specific rotation
of +- 47° (c=0.19 / MeOH). The Holton sequence to Taxol is relatively short compared to that of the other groups with an estimated 37 step not counting the addition of the amide tail. One of the reasons is that the patchoulol starting compound already contains 15 of the 20 carbon atoms required for the Taxol ABCD ring framework.
Other raw materials required for this synthesis include 4-pentenal, m-chloroperoxybenzoic acid
, methyl magnesium bromide
and phosgene
. Two key chemical transformations in this sequence are a Chan rearrangement
and a sulfonyloxaziridine enolate oxidation.
was derived from the natural product patchoulene oxide (1). The final stage of the synthesis was the formation of the tail by addition of the Ojima lactam
42 to alcohol 41. Of the four rings of Taxol, the D ring was formed last, the result of a simple intramolecular SN2 reaction of hydroxytosylate 33. Formation of the C ring took place through the Dieckmann condensation
of ketone 20, with a Grignard reagent
adding the final carbon for the ring system. Preparation for the C ring synthesis took place through a Chan rearrangement
of carbonate ester
13 and subsequent oxidation and reduction reactions
. The AB ring synthesis involved multiple rearrangements
starting from epoxide 1 (patchoulene oxide).
removed the acidic α-epoxide proton, leading to an elimination reaction
and ring-opening of the epoxide to give allylic alcohol
2. The allylic alcohol was epoxidized to epoxyalcohol 3 using tert-butyl hydroperoxide
and titanium(IV)tetraisopropoxide. In the subsequent reaction, the Lewis acid
boron trifluoride
catalyzed the ring opening of the epoxide followed by skeletal rearrangement of the isopropyl bridge and an elimination reaction to give unsaturated diol 4. The newly created hydroxyl group was protected as the triethylsilyl ether
, and the double bond was epoxidized by reaction with meta-cloroperbenzoic acid. Acid-catalization Grob fragmentation
of epoxide 6 gave ketone 7 in over 90% yield. The hydroxyl group was protected as the tert-butyldimethylsilyl ether
. In the next phase, the carbon atoms required for the formation of the C ring were added. The ketone group in 7 was converted into magnesium enolate 8 by action of lithium diisopropylamide
and methylmagnesium bromide. This enolate was reacted with 4-pentenal in an aldol reaction
to give β-hydroxyketone 9. The hydroxyl group was protected as the asymmetric carbonate ester
(10). Oxydation of the enolate of ketone 10 with (+)-camphorsulfonyl oxaziridine
gave α-hydroxyketone 11 in 85% yield. Reduction of the ketone group with 20 equivalents of Red-Al
gave a triol which was immediately converted to carbonate 12 using phosgene
.
of alcohol
12 gave ketone
13. The carbonyl group was used to set the functionality of the B ring in preparation for formation of the C ring. The first step in this sequence was a Chan rearrangement
of the carbonate ester
using lithium tetramethylpiperidide
, which gave α-hydroxyester 14. The hydroxyl group was reductively removed using samarium(II) iodide
to give stable enol 15. Chromatography of this enol on silica gel
gave the cis diastereomer 16 predominantly, along with a small amount of the trans isomer, which could be recycled. Treatment of this ketone with lithium tetramethylpiperidide
and (+)-camphorsulfonyl oxaziridine
gave α-hydroxyketone 17. Reduction of the ketone using Red-Al
resulted also in epimerization to give the required trans-fused lactone 18.
as a carbonate ester
(19). The terminal alkene group of 19 was next converted to a methyl ester
using ozonolysis
followed by oxidation with potassium permanganate
and esterification with diazomethane
. The second C-C bond formation step in the cyclohexane C ring synthesis involved a Dieckman condensation of lactone 20 using lithium diisopropylamide
as a base at -78°C to give enol
ester 21. Decarboxylation
of 21 required protection of the hydroxyl group as the 2-methoxy-2-propyl (MOP) ether (22). With the protecting group in place, decarboxylation was effected with potassium thiophenolate in dimethylformamide
to give protected hydroxy ketone 23. In the next two steps the MOP protecting group was removed by acid, and alcohol 24 was reprotected with another, more robust, ether protecting group, benzyloxymethyl (25). The ketone was converted to the trimethylsilyl
enol ether 26, which was subsequently oxidized in a Rubottom oxidation
using m-chloroperbezoic acid to give the trimethylsilyl protected acyloin
27. At this stage the final missing carbon atom in the Taxol ring framework was introduced in a Grignard reaction
of ketone 27 using a 10-fold excess of methylmagnesium bromide to give tertiary alcohol 28. Treatment of tertiary alcohol 28 with the Burgess reagent
gave the exocyclic alkene. Acidic workup gave allylic alcohol 29.
to give triol 30. The three hydroxyl groups were modified in the next five reaction steps.
After protection of the primary hydroxyl group, the secondary hydroxyl group in 32 was converted to a good leaving group using p-toluenesulfonyl chloride
. Tosylate 33 underwent cyclization to give oxetane 34 by nucleophilic displacement with inversion
of the tosyl group by the primary hydroxyl group. The remaining tertiary alcohol was acylated
, and the silyl group was removed to give allylic alcohol 36. The carbonate ester was cleaved by reaction with phenyllithium
in tetrahydrofuran
at -78°C to give alcohol 37, which completed the lower part of the B ring. In the upper part of the B ring, the hydroxyl group was oxidized to ketone 38 using tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine N-oxide (NMO)
. This ketone was depronated with potassium tert-butoxide in tetrahydrofuran at low temperature and further oxidized by reaction with benzeneseleninic anhydride to give α-hydroxyketone
39, which was subsequently acylated to give α-acetoxyketone 40.
. The hydroxyl group in 40 was deprotected to give alcohol 41. Reaction of the lithium alkoxide of 41 with the Ojima lactam
42 adds the tail in 43. Deprotection gave (-)-Taxol 45.
(45) and involved carbocation
rearrangement
followed by elimination
in the presence of a protic acid. The driving force for the rearrangement is relief of ring strain
. Zaitsev's rule
applies in the elimination. Epoxidization gave patchoulene oxide 1.
Deprotection Reagents: H2, Pd/C
Alcohol 25 (Scheme 3) was protected as the BOM ether, a more robust protecting group than MOP (see below).
, pyridine in dichloromethane followed by ethanol
Deprotection Reagents: Sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al
)
The secondary alcohol in the 4-pentenal product of the aldol reaction, 10 (Scheme 1), was protected by the asymmetric carbonate ester. This group was removed in conjunction with the Red-Al reduction of ketone 11 (Scheme 1).
, pyridine, dichloromethane, -78°C-25°C, 1 h
Deprotection Reagents: Chan rearrangement
with lithiumtetramethylpiperidide
Red-Al was used to completely reduce ketone 11 (Scheme 1) which caused carbonate rearrangement with elimination of ethanol. The cyclic carbonate ester was removed as a result of the Chan rearrangement in 13 which created a carbon-carbon bond that was part of Taxol.
, pyridine, dichloromethane, -23°C, 0.5 h
Deprotection Reagents: Phenyllithium
in tetrahydrofuran
at -78°C
Diol 19 (Scheme 3) was protected as a cyclic carbonate ester. This carbonate ester was cleaved by phenyllithium in tetrahydrofuran at -78°C to give hydroxybenzoate 36 (Scheme 4).
and 2-methoxypropene
Deprotection Reagents: Tetrabutylammonium fluoride (1 mol eq., THF, -1°C, 6 h)
The hydroxyl group in hydroxyester 21 (Scheme 3) was protected as a MOP ether in order to decarboxylate the β-ketoester group.
, tert-butyldimethylsilyl chloride
Deprotection Reagents: Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF)
After Grob fragmentation of β-epoxyalcohol 6 (Scheme 1), the resultant alcohol was protected as a TBS ether, which is kept in place until the final addition of the tail (Scheme 5).
Deprotection Reagents: Hydrogen fluoride/pyridine complex in acetonitrile
The secondary hydroxyl group in diol 4 (Scheme 1) was protected as a TES ether in order to prevent its participation in the Grob fragmentation of β-epoxyalcohol 6. The TES was cleaved in 36 (Scheme 4) and returned to the alcohol.
Deprotection Reagents: Hydrogen fluoride, pyridine
, acetonitrile
, 0°C, 1 h
The secondary alcohol on the tail of Taxol 43 (Scheme 5) needed to be protected until addition of the tail to the secondary hydroxyl group in ring A was complete.
, trimethylsilyl chloride
Deprotection Reagents: Burgess reagent
, acidic workup
Ketone 25 (Scheme 3) was protected as the TMS enol ether and subsequently was oxidized with M-chloroperoxybenzoic acid. In the process the TMS group migrated to the 2-hydroxyl group.
Deprotection Reagents: Acetic acid
The primary hydroxyl group in triol 30 (Scheme 4) was protected as a TMS ether allowing activation of the secondary hydroxyl group as a tosylate leaving group.
Robert A. Holton
Robert A. Holton is an American academic chemist who is known for his work regarding the chemical synthesis for Taxol , a widely-utilized and highly-effective anti-cancer drug. He is a Professor of Chemistry at Florida State University. Dr. Holton’s research group has accomplished the total...
and his group at Florida State University
Florida State University
The Florida State University is a space-grant and sea-grant public university located in Tallahassee, Florida, United States. It is a comprehensive doctoral research university with medical programs and significant research activity as determined by the Carnegie Foundation...
in 1994 was the first 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 (generic name: paclitaxel).
The Holton 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...
is a good example of a linear synthesis starting from commercially available natural compound patchoulene oxide.
This 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...
can be obtained in two steps from the terpene patchoulol
Patchoulol
Patchoulol or patchouli alcohol is a terpene extracted from Patchouli. The -optical isomer is one of the organic compounds responsible for the typical patchouli scent. Patchoulol is also used in the synthesis of the chemotherapy drug Taxol....
and also from borneol
Borneol
Borneol is a bicyclic organic compound and a terpene. The hydroxyl group in this compound is placed in an endo position.Borneol is easily oxidized to the ketone yielding camphor. One historical name for borneol is Borneo camphor which explains the name. Borneol can be synthesized by reduction of...
. The reaction sequence is also enantioselective, synthesizing (+)-Taxol from (-)-patchoulene oxide or (-)-Taxol from (-)-borneol with a reported specific rotation
Specific rotation
In stereochemistry, the specific rotation of a chemical compound [α] is defined as the observed angle of optical rotation α when plane-polarized light is passed through a sample with a path length of 1 decimeter and a sample concentration of 1 gram per 1 millilitre. It is the main property used to...
of +- 47° (c=0.19 / MeOH). The Holton sequence to Taxol is relatively short compared to that of the other groups with an estimated 37 step not counting the addition of the amide tail. One of the reasons is that the patchoulol starting compound already contains 15 of the 20 carbon atoms required for the Taxol ABCD ring framework.
Other raw materials required for this synthesis include 4-pentenal, m-chloroperoxybenzoic acid
Meta-Chloroperoxybenzoic acid
meta-Chloroperoxybenzoic acid is a peroxycarboxylic acid used widely as an oxidant in organic synthesis. mCPBA is often preferred to other peroxy acids because of its relative ease of handling...
, methyl magnesium bromide
Grignard reaction
The Grignard reaction is an organometallic chemical reaction in which alkyl- or aryl-magnesium halides add to a carbonyl group in an aldehyde or ketone. This reaction is an important tool for the formation of carbon–carbon bonds...
and phosgene
Phosgene
Phosgene is the chemical compound with the formula COCl2. This colorless gas gained infamy as a chemical weapon during World War I. It is also a valued industrial reagent and building block in synthesis of pharmaceuticals and other organic compounds. In low concentrations, its odor resembles...
. Two key chemical transformations in this sequence are a Chan rearrangement
Chan rearrangement
The Chan rearrangement is a chemical reaction that involves rearranging an acyloxy acetate in the presence of a strong base to a 2-hydroxy-3-keto-ester .This procedure was rediscovered and employed in the Holton Taxol total synthesis....
and a sulfonyloxaziridine enolate oxidation.
Retrosynthesis
Holton's total synthesis of TaxolPaclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
was derived from the natural product patchoulene oxide (1). The final stage of the synthesis was the formation of the tail by 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....
42 to alcohol 41. Of the four rings of Taxol, the D ring was formed last, the result of a simple intramolecular SN2 reaction of hydroxytosylate 33. Formation of the C ring took place through the Dieckmann condensation
Dieckmann condensation
The Dieckmann condensation is the intramolecular chemical reaction of diesters with base to give β-ketoesters. It is named after the German chemist Walter Dieckmann . The equivalent intermolecular reaction is the Claisen condensation....
of ketone 20, with a Grignard reagent
Grignard reaction
The Grignard reaction is an organometallic chemical reaction in which alkyl- or aryl-magnesium halides add to a carbonyl group in an aldehyde or ketone. This reaction is an important tool for the formation of carbon–carbon bonds...
adding the final carbon for the ring system. Preparation for the C ring synthesis took place through a Chan rearrangement
Chan rearrangement
The Chan rearrangement is a chemical reaction that involves rearranging an acyloxy acetate in the presence of a strong base to a 2-hydroxy-3-keto-ester .This procedure was rediscovered and employed in the Holton Taxol total synthesis....
of 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...
13 and subsequent oxidation and reduction reactions
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
. The AB ring synthesis involved multiple rearrangements
Rearrangement reaction
A rearrangement reaction is a broad class of organic reactions where the carbon skeleton of a molecule is rearranged to give a structural isomer of the original molecule. Often a substituent moves from one atom to another atom in the same molecule...
starting from epoxide 1 (patchoulene oxide).
| Retrosynthesis |
|---|
AB Ring synthesis
As shown in Scheme 1, starting from patchoulene oxide (1), the first steps created the bicyclo[5.3.1]undecane AB ring system of Taxol. Reaction of epoxide 1 with tert-butyllithiumTert-Butyllithium
tert-Butyllithium is a chemical compound with the formula 3CLi. As an organometallic compound, it has applications in organic synthesis since it is a sufficiently strong base to deprotonate many carbon acids, including benzene...
removed the acidic α-epoxide proton, leading to 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...
and ring-opening of the epoxide to give allylic alcohol
Allyl alcohol
Allyl alcohol is an organic compound with the structural formula CH2=CHCH2OH. Like many alcohols,it is a water soluble, colourless liquid, but it is more toxic than typical small alcohols. Allyl alcohol is used as a raw material for the production of glycerol, but is used as a precursor to many...
2. The allylic alcohol was epoxidized to epoxyalcohol 3 using tert-butyl hydroperoxide
Tert-Butyl hydroperoxide
tert-Butyl hydroperoxide is an organic peroxide widely used in a variety of oxidation processes, for example Sharpless epoxidation...
and titanium(IV)tetraisopropoxide. In the subsequent reaction, the Lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...
boron trifluoride
Boron trifluoride
Boron trifluoride is the chemical compound with the formula BF3. This pungent colourless toxic gas forms white fumes in moist air. It is a useful Lewis acid and a versatile building block for other boron compounds.-Structure and bonding:...
catalyzed the ring opening of the epoxide followed by skeletal rearrangement of the isopropyl bridge and an elimination reaction to give unsaturated diol 4. The newly created hydroxyl group was protected as the triethylsilyl 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...
, and the double bond was epoxidized by reaction with meta-cloroperbenzoic acid. Acid-catalization 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...
of epoxide 6 gave ketone 7 in over 90% yield. The hydroxyl group was protected as the 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...
. In the next phase, the carbon atoms required for the formation of the C ring were added. The ketone group in 7 was converted into magnesium enolate 8 by action of lithium diisopropylamide
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...
and methylmagnesium bromide. This enolate was reacted with 4-pentenal in an 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...
to give β-hydroxyketone 9. The hydroxyl group was protected as the asymmetric 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...
(10). Oxydation of the enolate of ketone 10 with (+)-camphorsulfonyl 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...
gave α-hydroxyketone 11 in 85% yield. Reduction of the ketone group with 20 equivalents of Red-Al
Red-Al
Red-Al, or sodium bisaluminumhydride, is an organoaluminium compound with the formula NaAlH22. The name which is a trademark of Sigma-Aldrich refers to its being a Reducing aluminium compound. It is used almost exclusively as a solution in toluene, which is used as a reagent in organic synthesis...
gave a triol which was immediately converted to carbonate 12 using phosgene
Phosgene
Phosgene is the chemical compound with the formula COCl2. This colorless gas gained infamy as a chemical weapon during World War I. It is also a valued industrial reagent and building block in synthesis of pharmaceuticals and other organic compounds. In low concentrations, its odor resembles...
.
| Scheme 1 |
|---|
C Ring preparation
As shown in Scheme 2, Swern oxidationSwern 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 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....
12 gave 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...
13. The carbonyl group was used to set the functionality of the B ring in preparation for formation of the C ring. The first step in this sequence was a Chan rearrangement
Chan rearrangement
The Chan rearrangement is a chemical reaction that involves rearranging an acyloxy acetate in the presence of a strong base to a 2-hydroxy-3-keto-ester .This procedure was rediscovered and employed in the Holton Taxol total synthesis....
of 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...
using lithium tetramethylpiperidide
Lithium tetramethylpiperidide
Lithium tetramethylpiperidide or LiTMP is an organic base and a non-nucleophilic base. It is traditionally synthesised from 2,2,6,6-tetramethylpiperidine and n-butyllithium at -78 °C, but recent reports show this reaction is sluggish and is better formed at 0 °C. The compound is stable in a...
, which gave α-hydroxyester 14. The hydroxyl group was reductively removed using 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...
to give stable enol 15. Chromatography of this enol on silica gel
Silica gel
Silica gel is a granular, vitreous, porous form of silica made synthetically from sodium silicate. Despite its name, silica gel is a solid. It is a naturally occurring mineral that is purified and processed into either granular or beaded form...
gave the cis diastereomer 16 predominantly, along with a small amount of the trans isomer, which could be recycled. Treatment of this ketone with lithium tetramethylpiperidide
Lithium tetramethylpiperidide
Lithium tetramethylpiperidide or LiTMP is an organic base and a non-nucleophilic base. It is traditionally synthesised from 2,2,6,6-tetramethylpiperidine and n-butyllithium at -78 °C, but recent reports show this reaction is sluggish and is better formed at 0 °C. The compound is stable in a...
and (+)-camphorsulfonyl 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...
gave α-hydroxyketone 17. Reduction of the ketone using Red-Al
Red-Al
Red-Al, or sodium bisaluminumhydride, is an organoaluminium compound with the formula NaAlH22. The name which is a trademark of Sigma-Aldrich refers to its being a Reducing aluminium compound. It is used almost exclusively as a solution in toluene, which is used as a reagent in organic synthesis...
resulted also in epimerization to give the required trans-fused lactone 18.
| Scheme 2 |
|---|
C Ring synthesis
As shown in Scheme 3, diol 18 was protected with phosgenePhosgene
Phosgene is the chemical compound with the formula COCl2. This colorless gas gained infamy as a chemical weapon during World War I. It is also a valued industrial reagent and building block in synthesis of pharmaceuticals and other organic compounds. In low concentrations, its odor resembles...
as 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...
(19). The terminal alkene group of 19 was next converted to a methyl 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...
using 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...
followed by oxidation with potassium permanganate
Permanganate
A permanganate is the general name for a chemical compound containing the manganate ion, . Because manganese is in the +7 oxidation state, the permanganate ion is a strong oxidizing agent. The ion has tetrahedral geometry...
and esterification with diazomethane
Diazomethane
Diazomethane is the chemical compound CH2N2. It is the simplest of diazo compounds. In the pure form at room temperature, it is a extremely sensitive explosive yellow gas, thus it is almost universally used as a solution in diethyl ether...
. The second C-C bond formation step in the cyclohexane C ring synthesis involved a Dieckman condensation of lactone 20 using lithium diisopropylamide
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...
as a base at -78°C to give 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...
ester 21. Decarboxylation
Decarboxylation
Decarboxylation is a chemical reaction that releases carbon dioxide . Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carbonation, the addition of CO2 to...
of 21 required protection of the hydroxyl group as the 2-methoxy-2-propyl (MOP) ether (22). With the protecting group in place, decarboxylation was effected with potassium thiophenolate in dimethylformamide
Dimethylformamide
Dimethylformamide is an organic compound with the formula 2NCH. Commonly abbreviated as DMF , this colourless liquid is miscible with water and the majority of organic liquids. DMF is a common solvent for chemical reactions...
to give protected hydroxy ketone 23. In the next two steps the MOP protecting group was removed by acid, and alcohol 24 was reprotected with another, more robust, ether protecting group, benzyloxymethyl (25). The ketone was converted to 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...
enol ether 26, which was subsequently oxidized in a Rubottom oxidation
Rubottom oxidation
The Rubottom oxidation is the chemical reaction of enolsilanes with m-chloroperoxybenzoic acid to give silyl-protected α-hydroxy ketones.-Reaction mechanism:...
using m-chloroperbezoic acid to give the trimethylsilyl protected 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:...
27. At this stage the final missing carbon atom in the Taxol ring framework was introduced in a Grignard reaction
Grignard reaction
The Grignard reaction is an organometallic chemical reaction in which alkyl- or aryl-magnesium halides add to a carbonyl group in an aldehyde or ketone. This reaction is an important tool for the formation of carbon–carbon bonds...
of ketone 27 using a 10-fold excess of methylmagnesium bromide to give tertiary alcohol 28. Treatment of tertiary alcohol 28 with the Burgess reagent
Burgess reagent
The Burgess reagent or methyl N-carbamate was developed in the laboratory of Edward M. Burgess at Georgia Tech. It is a mild and selective dehydrating reagent often used in organic chemistry. It is used to convert secondary and tertiary alcohol with an adjacent proton into alkenes. Primary alcohols...
gave the exocyclic alkene. Acidic workup gave allylic alcohol 29.
| Scheme 3 |
|---|
D Ring synthesis and AB ring elaboration
In this section of the Holton Taxol synthesis (Scheme 4) the oxetane D ring was completed and ring B was functionalized with the correct substituents. Allylic alcohol 29 was oxidized with osmium tetroxide in pyridinePyridine
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 give triol 30. The three hydroxyl groups were modified in the next five reaction steps.
After protection of the primary hydroxyl group, the secondary hydroxyl group in 32 was converted to a good leaving group using p-toluenesulfonyl chloride
4-Toluenesulfonyl chloride
4-Toluenesulfonyl chloride is an organic compound with the formula CH3C6H4SO2Cl. This colourless, malodorous solid is a reagent widely used in organic synthesis...
. Tosylate 33 underwent cyclization to give oxetane 34 by nucleophilic displacement with inversion
Walden inversion
Walden inversion is the inversion of a chiral center in a molecule in a chemical reaction. Since a molecule can form two enantiomers around a chiral center, the Walden inversion converts the configuration of the molecule from one enantiomeric form to the other. For example, in a SN2 reaction,...
of the tosyl group by the primary hydroxyl group. The remaining tertiary alcohol was acylated
Acylation
In chemistry, acylation is the process of adding an acyl group to a compound. The compound providing the acyl group is called the acylating agent....
, and the silyl group was removed to give allylic alcohol 36. The carbonate ester was cleaved 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...
in 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...
at -78°C to give alcohol 37, which completed the lower part of the B ring. In the upper part of the B ring, the hydroxyl group was oxidized to ketone 38 using tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine N-oxide (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...
. This ketone was depronated with potassium tert-butoxide in tetrahydrofuran at low temperature and further oxidized by reaction with benzeneseleninic anhydride to give α-hydroxyketone
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:...
39, which was subsequently acylated to give α-acetoxyketone 40.
| Scheme 4 |
|---|
Tail addition
The tail addition step in this synthesis (Scheme 5) is identical to that in the Nicolaou tail addition and based on the Ojima lactamOjima 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 hydroxyl group in 40 was deprotected to give alcohol 41. Reaction of the lithium alkoxide of 41 with 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....
42 adds the tail in 43. Deprotection gave (-)-Taxol 45.
| Scheme 5 |
|---|
Precursor synthesis
The synthesis of patchoulene oxide (1) started from tricyclic compound patchoulolPatchoulol
Patchoulol or patchouli alcohol is a terpene extracted from Patchouli. The -optical isomer is one of the organic compounds responsible for the typical patchouli scent. Patchoulol is also used in the synthesis of the chemotherapy drug Taxol....
(45) and involved carbocation
Carbocation
A carbocation is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability . Therefore carbocations are often reactive,...
rearrangement
Rearrangement reaction
A rearrangement reaction is a broad class of organic reactions where the carbon skeleton of a molecule is rearranged to give a structural isomer of the original molecule. Often a substituent moves from one atom to another atom in the same molecule...
followed by elimination
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...
in the presence of a protic acid. The driving force for the rearrangement is relief of ring strain
Ring strain
In organic chemistry, ring strain is the tendency of a cyclic molecule, such as cyclopropane, to destabilize when its atoms are in non-favorable high energy spatial orientations...
. Zaitsev's rule
Zaitsev's rule
In chemistry, Zaitsev's rule, Saytzeff's rule or Saytsev's rule named after Alexander Mikhailovich Zaitsev is a rule that states that if more than one alkene can be formed during dehalogenation by an elimination reaction, the more stable alkene is the major product...
applies in the elimination. Epoxidization gave patchoulene oxide 1.
BOM (benzyloxymethyl)
Protection Reagents: Benzyloxymethyl chloride, N,N-diisopropylethanamine, tetrabutylammonium iodide, reflux 32 hDeprotection Reagents: H2, Pd/C
Alcohol 25 (Scheme 3) was protected as the BOM ether, a more robust protecting group than MOP (see below).
Carbonate (asymmetric)
Protection Reagents: PhosgenePhosgene
Phosgene is the chemical compound with the formula COCl2. This colorless gas gained infamy as a chemical weapon during World War I. It is also a valued industrial reagent and building block in synthesis of pharmaceuticals and other organic compounds. In low concentrations, its odor resembles...
, pyridine in dichloromethane followed by ethanol
Deprotection Reagents: Sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al
Red-Al
Red-Al, or sodium bisaluminumhydride, is an organoaluminium compound with the formula NaAlH22. The name which is a trademark of Sigma-Aldrich refers to its being a Reducing aluminium compound. It is used almost exclusively as a solution in toluene, which is used as a reagent in organic synthesis...
)
The secondary alcohol in the 4-pentenal product of the aldol reaction, 10 (Scheme 1), was protected by the asymmetric carbonate ester. This group was removed in conjunction with the Red-Al reduction of ketone 11 (Scheme 1).
Carbonate (cyclic) [1]
Protection Reagent: PhosgenePhosgene
Phosgene is the chemical compound with the formula COCl2. This colorless gas gained infamy as a chemical weapon during World War I. It is also a valued industrial reagent and building block in synthesis of pharmaceuticals and other organic compounds. In low concentrations, its odor resembles...
, pyridine, dichloromethane, -78°C-25°C, 1 h
Deprotection Reagents: Chan rearrangement
Chan rearrangement
The Chan rearrangement is a chemical reaction that involves rearranging an acyloxy acetate in the presence of a strong base to a 2-hydroxy-3-keto-ester .This procedure was rediscovered and employed in the Holton Taxol total synthesis....
with lithiumtetramethylpiperidide
Red-Al was used to completely reduce ketone 11 (Scheme 1) which caused carbonate rearrangement with elimination of ethanol. The cyclic carbonate ester was removed as a result of the Chan rearrangement in 13 which created a carbon-carbon bond that was part of Taxol.
Carbonate (cyclic) [2]
Protection Reagent: PhosgenePhosgene
Phosgene is the chemical compound with the formula COCl2. This colorless gas gained infamy as a chemical weapon during World War I. It is also a valued industrial reagent and building block in synthesis of pharmaceuticals and other organic compounds. In low concentrations, its odor resembles...
, pyridine, dichloromethane, -23°C, 0.5 h
Deprotection Reagents: 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...
in 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...
at -78°C
Diol 19 (Scheme 3) was protected as a cyclic carbonate ester. This carbonate ester was cleaved by phenyllithium in tetrahydrofuran at -78°C to give hydroxybenzoate 36 (Scheme 4).
MOP (2-methoxy-2-propyl)
Protection Reagents: p-Toluenesulfonic acidP-Toluenesulfonic acid
p-Toluenesulfonic acid or tosylic acid is an organic compound with the formula CH3C6H4SO3H. It is a white solid that is soluble in water, alcohols, and other polar organic solvents. The 4-CH3C6H4SO2- group is known as the Tosyl group and is often abbreviated as Ts or Tos...
and 2-methoxypropene
Deprotection Reagents: Tetrabutylammonium fluoride (1 mol eq., THF, -1°C, 6 h)
The hydroxyl group in hydroxyester 21 (Scheme 3) was protected as a MOP ether in order to decarboxylate the β-ketoester group.
TBS (tert-butyldimethylsilyl)
Protection Reagents: Butyllithium, 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...
, tert-butyldimethylsilyl chloride
Deprotection Reagents: Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF)
After Grob fragmentation of β-epoxyalcohol 6 (Scheme 1), the resultant alcohol was protected as a TBS ether, which is kept in place until the final addition of the tail (Scheme 5).
TES (triethylsilyl) [1]
Protection Reagents: Triethylsilyl chloride, 4-(dimethylamino)pyridine, pyridinePyridine
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...
Deprotection Reagents: Hydrogen fluoride/pyridine complex in acetonitrile
Acetonitrile
Acetonitrile is the chemical compound with formula . This colourless liquid is the simplest organic nitrile. It is produced mainly as a byproduct of acrylonitrile manufacture...
The secondary hydroxyl group in diol 4 (Scheme 1) was protected as a TES ether in order to prevent its participation in the Grob fragmentation of β-epoxyalcohol 6. The TES was cleaved in 36 (Scheme 4) and returned to the alcohol.
TES (triethylsilyl) [2]
Protection Reagents: See Ojima lactamOjima 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....
Deprotection Reagents: Hydrogen fluoride, 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...
, acetonitrile
Acetonitrile
Acetonitrile is the chemical compound with formula . This colourless liquid is the simplest organic nitrile. It is produced mainly as a byproduct of acrylonitrile manufacture...
, 0°C, 1 h
The secondary alcohol on the tail of Taxol 43 (Scheme 5) needed to be protected until addition of the tail to the secondary hydroxyl group in ring A was complete.
TMS (trimethylsilyl) [1]
Protection Reagents: Lithium diisopropylamideLithium 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...
, 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...
Deprotection Reagents: Burgess reagent
Burgess reagent
The Burgess reagent or methyl N-carbamate was developed in the laboratory of Edward M. Burgess at Georgia Tech. It is a mild and selective dehydrating reagent often used in organic chemistry. It is used to convert secondary and tertiary alcohol with an adjacent proton into alkenes. Primary alcohols...
, acidic workup
Ketone 25 (Scheme 3) was protected as the TMS enol ether and subsequently was oxidized with M-chloroperoxybenzoic acid. In the process the TMS group migrated to the 2-hydroxyl group.
TMS (trimethylsilyl) [2]
Protection Reagents: Trimethylsilyl chlorideTrimethylsilyl 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...
Deprotection Reagents: 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...
The primary hydroxyl group in triol 30 (Scheme 4) was protected as a TMS ether allowing activation of the secondary hydroxyl group as a tosylate leaving group.
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...
- 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'....
- 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...