The Kuwajima Taxol total synthesis by the group of Isao Kuwajima of the

Tokyo Institute of Technology The Tokyo Institute of Technology () was a public university in Meguro, Tokyo, Japan. It merged with Tokyo Medical and Dental University to form the Institute of Science Tokyo on 1 October 2024. The Tokyo Institute of Technology was a De ...

is one of several efforts in taxol total synthesis published in the 1990s. The

total synthesis Total synthesis, a specialized area within organic chemistry, focuses on constructing complex organic compounds, especially those found in nature, using laboratory methods. It often involves synthesizing natural products from basic, commercially ...

Taxol Paclitaxel, sold under the brand name Taxol among others, is a chemotherapy medication used to treat ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. It is administered by ...

is considered a landmark in

organic synthesis Organic synthesis is a branch of chemical synthesis concerned with the construction of organic compounds. Organic compounds are molecules consisting of combinations of covalently-linked hydrogen, carbon, oxygen, and nitrogen atoms. Within the gen ...

. This synthesis is truly synthetic without any help from small biomolecule precursors and also a

linear synthesis In chemistry a convergent synthesis is a strategy that aims to improve the efficiency of multistep synthesis, most often in organic synthesis. In this type of synthesis several individual pieces of a complex molecule are synthesized in stage one, an ...

with molecule ring construction in the order of A, B, C, D. At some point

chirality Chirality () is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable fro ...

is locked into the molecule via an

asymmetric synthesis Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecul ...

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 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 reacti ...

. The 20 carbon frame is constructed from several pieces:

propargyl alcohol Propargyl alcohol, or 2-propyn-1-ol, is an organic compound with the formula C3H4O. It is the simplest stable alcohol containing an alkyne functional group. Propargyl alcohol is a colorless viscous liquid that is miscible with water and most pol ...

(C1, C2, C14),

propionaldehyde Propionaldehyde or propanal is the organic compound with the formula CH3CH2CHO. It is the 3-carbon aldehyde. It is a colourless, flammable liquid with a pungent and fruity odour. It is produced on a large scale industrially. Production Propiona ...

(C13, C12, C18),

isobutyric acid Isobutyric acid, also known as 2-methylpropanoic acid or isobutanoic acid, is a carboxylic acid with structural formula ( CH3)2CH COOH. It is an isomer of butyric acid. It is classified as a short-chain fatty acid. Deprotonation or esterificati ...

(C15, C16, C17, C11), Trimethyl(phenylthiomethyl)silane (C10), 2-bromobenzaldehyde (C3 to C9),

diethylaluminum cyanide Diethylaluminium cyanide ("Nagata's reagent") is the organoaluminium compound with formula . This colorless compound is usually handled as a solution in toluene. It is a reagent for the hydrocyanation of α,β-unsaturated ketones. Synthesis Diet ...

(C19) and trimethylsilylmethyl bromide (C20)

Synthesis A ring

Ring A synthesis (''scheme 1'') started by joining the THP protected

1.1 (the C2-C1-C14 fragment) and

1.2 (fragment C13-C12-C18) in a

nucleophilic addition In organic chemistry, a nucleophilic addition (AN) reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic addit ...

with ''n''-butyllithium to

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

1.3. The

Lindlar catalyst A Lindlar catalyst is a heterogeneous catalyst consisting of palladium deposited on calcium carbonate or barium sulfate then poisoned with various forms of lead or sulfur. It is used for the hydrogenation of alkynes to alkenes (i.e. without furth ...

then

reduced Reduction, reduced, or reduce may refer to: Science and technology Chemistry * Reduction (chemistry), part of a reduction-oxidation (redox) reaction in which atoms have their oxidation state changed. ** Organic redox reaction, a redox reacti ...

the

alkyne \ce \ce Acetylene \ce \ce \ce Propyne \ce \ce \ce \ce 1-Butyne In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and n ...

to the

alkene In organic chemistry, an alkene, or olefin, is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or at the terminal position. Terminal alkenes are also known as Alpha-olefin, α-olefins. The Internationa ...

in 1.4 and

Swern oxidation In organic chemistry, the Swern oxidation also known as Moffatt-Swern, named after Daniel Swern, is a chemical reaction whereby a primary or secondary Alcohol (chemistry), alcohol () is redox, oxidized to an aldehyde () or ketone () using oxalyl ...

converted the alcohol group to the enone group in 1.5. Fragment C11-C15-C16-C17 1.6 was then added as the lithium

enol In organic chemistry, enols are a type of functional group or intermediate in organic chemistry containing a group with the formula (R = many substituents). The term ''enol'' is an abbreviation of ''alkenol'', a portmanteau deriving from "-ene ...

ate of

ethyl

ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

in a

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 polar ...

to gamma keto ester 1.7. A

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. The reaction produces a β-keto ester or a β- diketone. It is named ...

closed the ring to 1.8 and the intermediate enol is captured by

pivaloyl chloride 2,2-Dimethylpropanoyl chloride is a branched-chain acyl chloride. It was first made by Aleksandr Butlerov in 1874 by reacting pivalic acid with phosphorus pentachloride Phosphorus pentachloride is the chemical compound with the formula . It is ...

(piv) as a

protective group A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis. In man ...

. The THP group was removed with TsOH to 1.9 and the formed

oxidized by

aldehyde In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...

1.10. The TIPS

silyl enol ether In organosilicon chemistry, silyl enol ethers are a class of organic compounds that share the common functional group , composed of an enolate () bonded to a silane () through its oxygen end and an ethene group () as its carbon end. They are i ...

1.11 was formed by reaction with the

triflate In organic chemistry, triflate (Preferred IUPAC name, systematic name: trifluoromethanesulfonate), is a functional group with the Chemical formula, formula and Chemical structure, structure . The triflate group is often represented by , as opp ...

TIPSOtf and

DBU DBU may refer to: Universities * Dallas Baptist University, Dallas, Texas, U.S. * Desh Bhagat University, Mandi Gobindgarh, Punjab, India * Duluth Business University, Duluth, Minnesota, U.S. Other uses * 1,8-Diazabicyclo .4.0ndec-7-ene, an org ...

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 In organic chemistry, an aminal or aminoacetal is a functional group or type of organic compound that has two amine groups attached to the same carbon atom: . (As is customary in organic chemistry, R can represent hydrogen or an alkyl group). A ...

1.13 and as this group is automatically lost on

column chromatography Column chromatography in chemistry is a chromatography method used to isolate a single chemical compounds, chemical compound from a mixture. Chromatography is able to separate substances based on differential absorption of compounds to the adsorbe ...

, 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 Sulfide (also sulphide in British English) is an inorganic anion of sulfur with the chemical formula S2− or a compound containing one or more S2− ions. Solutions of sulfide salts are corrosive. ''Sulfide'' also refers to large families o ...

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.

Synthesis B ring

The bottom part of ring B was constructed by

to the aldehyde of 2.1 (''scheme 2'') with dibenzyl

acetal In organic chemistry, an acetal is a functional group with the connectivity . Here, the R groups can be organic fragments (a carbon atom, with arbitrary other atoms attached to that) or hydrogen, while the R' groups must be organic fragments n ...

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 A diol is a chemical compound containing two hydroxyl groups ( groups). An aliphatic diol may also be called a glycol. This pairing of functional groups is pervasive, and many subcategories have been identified. They are used as protecting gro ...

in 2.3 was protected as the

boronic ester A boronic acid is an organic compound related to boric acid () in which one of the three hydroxyl groups () is replaced by an alkyl or aryl group (represented by R in the general formula ). As a compound containing a carbon–boron bond, memb ...

2.4 preparing the molecule for upper part ring closure with

tin tetrachloride Tin(IV) chloride, also known as tin tetrachloride or stannic chloride, is an inorganic compound of tin and chlorine with the formula SnCl4. It is a colorless hygroscopic liquid, which fumes on contact with air. It is used as a precursor to other ...

to tricycle 2.5 in a

Grob fragmentation A Grob fragmentation is an elimination reaction that breaks a neutral aliphatic chain into three fragments: a cation, positive ion spanning atoms 1 and 2 (the "electrofuge"), an unsaturated hydrocarbon, unsaturated neutral fragment spanning positio ...

-like reaction. After deprotection (

pinacol Pinacol is a branched alcohol which finds use in organic syntheses. It is a diol that has hydroxyl groups on vicinal carbon atoms. A white solid that melts just above room temperature, pinacol is notable for undergoing the pinacol rearrangement ...

) to diol 2.6,

DIBAL Diisobutylaluminium hydride (DIBALH, DIBAL, DIBAL-H or DIBAH) is a reducing agent with the formula (''i''-Bu2AlH)2, where ''i''-Bu represents isobutyl (-CH2CH(CH3)2). This organoaluminium compound is a reagent in organic synthesis. Properties Like ...

reduction to triol 2.7 and TBS reprotection (TBSOtf,

lutidine Lutidine is the trivial name used to describe the chemical compounds which are dimethyl derivatives of pyridine. They were discovered in Dippel's oil and named (as an anagram of toluidine, with which they share their empirical formula) by Thomas ...

) to alcohol 2.8 it was possible to remove the phenylsulfide group in with a

tributyltin hydride Tributyltin hydride is an organotin compound with the formula (C4H9)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 The c ...

and AIBN(see Barton-McCombie deoxygenation) to alcohol 2.9.

Palladium on carbon Palladium on carbon, often referred to as Pd/C, is a form of palladium used as a catalyst. The metal is supported on activated carbon to maximize its surface area and activity. Uses Hydrogenation Palladium on carbon is used for catalytic hydrog ...

hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to redox, reduce or Saturated ...

removed the benzyl protecting group allowing the

of 2.10 to ketone 2.11

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 reduction The Birch reduction or Metal-Ammonia reduction is an organic reaction that is used to convert arenes to Cyclohexa-1,4-diene, 1,4-cyclohexadienes. The reaction is named after the Australian chemist Arthur Birch (organic chemist), Arthur Birch and i ...

(

potassium Potassium is a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...

ammonia Ammonia is an inorganic chemical compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride and the simplest pnictogen hydride, ammonia is a colourless gas with a distinctive pu ...

tetrahydrofuran Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...

, -78 °C, then

ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...

) to

diene In organic chemistry, a diene ( ); also diolefin, ) or alkadiene) is a covalent compound that contains two double bonds, usually among carbon atoms. They thus contain two alk''ene'' units, with the standard prefix ''di'' of systematic nome ...

3.2. Deprotection (

TBAF Tetra-''n''-butylammonium fluoride, commonly abbreviated to TBAF and ''n''-Bu4NF, is a quaternary ammonium salt with the chemical formula (CH3CH2CH2CH2)4N+F−. It is commercially available as the white solid trihydrate and as a solution in tetra ...

) to diol 3.3, reprotection as the

benzaldehyde Benzaldehyde (C6H5CHO) is an organic compound consisting of a benzene ring with a formyl substituent. It is among the simplest aromatic aldehydes and one of the most industrially useful. It is a colorless liquid with a characteristic almond-li ...

3.4 and reduction (

sodium borohydride Sodium borohydride, also known as sodium tetrahydridoborate and sodium tetrahydroborate, is an inorganic compound with the formula (sometimes written as ). It is a white crystalline solid, usually encountered as an aqueous basic solution. Sodi ...

) to alcohol 3.5 allowed the oxidation of the diene to the 1,4-butenediol 3.6. In this

photochemical Photochemistry is the branch of chemistry concerned with the chemical effects of light. Generally, this term is used to describe a chemical reaction caused by absorption of ultraviolet (wavelength from 100 to 400 nm), visible (400–750&nb ...

+2 ycloaddition,

singlet oxygen Singlet oxygen, systematically named dioxygen(singlet) and dioxidene, is a gaseous inorganic chemistry, inorganic chemical with the formula O=O (also written as or ), which is in a quantum state where all electrons are Radical (chemistry), spin p ...

was generated from oxygen and

rose bengal Rose bengal (4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein) is a staining (biology), stain. Rose bengal belongs to the class of organic compounds called xanthenes. Its sodium salt is commonly used in eye drops to stain damaged conjuncti ...

and the intermediate

peroxide In chemistry, peroxides are a group of Chemical compound, compounds with the structure , where the R's represent a radical (a portion of a complete molecule; not necessarily a free radical) and O's are single oxygen atoms. Oxygen atoms are joined ...

was reduced with

thiourea Thiourea () is an organosulfur compound with the formula and the structure . It is structurally similar to urea (), with the oxygen atom replaced by sulfur atom (as implied by the '' thio-'' prefix). The properties of urea and thiourea differ s ...

. The next order of business was introduction of the C19 fragment: the new diol group was protected as the PMP

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 Diethylaluminium cyanide ("Nagata's reagent") is the organoaluminium compound with formula . This colorless compound is usually handled as a solution in toluene. It is a reagent for the hydrocyanation of α,β-unsaturated ketones. Synthesis Diet ...

reacted in a

to the enone group to

nitrile In organic chemistry, a nitrile is any organic compound that has a functional group. The name of the compound is composed of a base, which includes the carbon of the , suffixed with "nitrile", so for example is called " propionitrile" (or pr ...

3.9. The enol was protected as the TBS ether 3.10 allowing for the reduction of the nitrile group first to the

with

and then on to the

3.11 with

Lithium aluminium hydride Lithium aluminium hydride, commonly abbreviated to LAH, is an inorganic compound with the chemical formula or . It is a white solid, discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic synthe ...

. The alcohol group was replaced by bromine in an

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 car ...

which caused an

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. The one-step mechanism is known as the E2 reaction, and the two-step mechanism is known as the E1 r ...

(loss of HBr) to

cyclopropane Cyclopropane is the cycloalkane with the molecular formula (CH2)3, consisting of three methylene groups (CH2) linked to each other to form a triangular ring. The small size of the ring creates substantial ring strain in the structure. Cyclopropane ...

3.12. Treatment with

hydrochloric acid Hydrochloric acid, also known as muriatic acid or spirits of salt, is an aqueous solution of hydrogen chloride (HCl). It is a colorless solution with a distinctive pungency, pungent smell. It is classified as a acid strength, strong acid. It is ...

formed ketone 3.13, reaction with

Samarium(II) iodide Samarium(II) iodide is an inorganic compound with the formula SmI2. When employed as a solution for organic synthesis, it is known as Kagan's reagent. SmI2 is a green solid and forms a dark blue solution in THF. It is a strong one-electron re ...

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

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 peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...

sodium bicarbonate Sodium bicarbonate ( IUPAC name: sodium hydrogencarbonate), commonly known as baking soda or bicarbonate of soda (or simply “bicarb” especially in the UK) is a chemical compound with the formula NaHCO3. It is a salt composed of a sodium cat ...

) 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 In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl () compounds. Rarely isolated, they are widely used as reagents in the Organic synthesis, synthesis of organic compounds. Bonding and structure Enolate ...

4.7 by reaction with KHMDS and

N,N-bis(trifluoromethylsulfonyl)aniline In organic chemistry, triflate (systematic name: trifluoromethanesulfonate), is a functional group with the formula and structure . The triflate group is often represented by , as opposed to −Tf, which is the triflyl group, . For example, ...

. These preambles facilitated the introduction of the final missing C20 fragment as the

Grignard reagent Grignard reagents or Grignard compounds are chemical compounds with the general formula , where X is a halogen and R is an organic group, normally an alkyl or aryl. Two typical examples are methylmagnesium chloride and phenylmagnesium bromi ...

''trimethylsilylmethylmagnesium bromide'' which

coupled ''Coupled'' is an American dating game show that aired on Fox from May 17 to August 2, 2016. It was hosted by television personality, Terrence J and created by Mark Burnett, of '' Survivor'', '' The Apprentice'', '' Are You Smarter than a 5th ...

with the triflate in a

tetrakis(triphenylphosphine)palladium(0) Tetrakis(triphenylphosphine)palladium(0) (sometimes called quatrotriphenylphosphine palladium) is the chemical compound d(P(C6H5)3)4 often abbreviated Pd( PPh3)4, or rarely PdP4. It is a bright yellow crystalline solid that becomes brown upon d ...

catalysed reaction to the

silane Silane (Silicane) is an inorganic compound with chemical formula . It is a colorless, pyrophoric gas with a sharp, repulsive, pungent smell, somewhat similar to that of acetic acid. Silane is of practical interest as a precursor to elemental ...

4.8. The

trimethylsilyl A trimethylsilyl group (abbreviated TMS) is a functional group in organic chemistry. This group consists of three methyl groups bonded to a silicon atom minus;Si(CH3)3 which is in turn bonded to the rest of a molecule. This structural group i ...

group eliminated on addition of NCS to

organochloride Organochlorine chemistry is concerned with the properties of organochlorine compounds, or organochlorides, organic compounds that contain one or more carbon–chlorine bonds. The chloroalkane class (alkanes with one or more hydrogens substituted ...

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, a subdiscipline of chemistry, studies the spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereoisomers, which are defined ...

. After

acetylation : In chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply ''acetates''. Deacetylation is the opposite react ...

to 4.11 and inversion of configuration with added base DBN this problem was remedied in compound 4.12. Next

dihydroxylation Dihydroxylation is the process by which an alkene is converted into a vicinal (chemistry), vicinal diol. Although there are many routes to accomplish this oxidation, the most common and direct processes use a high-oxidation-state transition metal ...

with

Osmium(VIII) oxide Osmium tetroxide (also osmium(VIII) oxide) is the chemical compound with the formula OsO4. The compound is noteworthy for its many uses, despite its toxicity and the rarity of osmium. It also has a number of unusual properties, one being that the ...

formed the

4.13 with the primary alcohol on addition of base

displacing the chlorine atom in a

nucleophilic aliphatic substitution In chemistry, a nucleophilic substitution (SN) is a class of chemical reactions in which an electron-rich chemical species (known as a nucleophile) replaces a functional group within another electron-deficient molecule (known as the electrophile). ...

oxetane Oxetane, or 1,3-propylene oxide, is a heterocycle, heterocyclic organic compound with the molecular formula , having a four-membered ring with three carbon atoms and one oxygen atom. The term "an oxetane" or "oxetanes" refer to any organic compou ...

4.14.

Tail addition

The C1, C2 and C4 functional groups were put in place next and starting from

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

group was removed in 5.4 (

PdOH₂, H₂) and replaced by a

carbonate ester In organic chemistry, a carbonate ester (organic carbonate or organocarbonate) is an ester of carbonic acid. This functional group consists of a carbonyl group flanked by two alkoxy groups. The general structure of these carbonates is and they a ...

group in 5.5 (

triphosgene Triphosgene (bis(trichloromethyl) carbonate (BTC)) is a chemical compound with the formula OC(OCCl3)2. It is used as a solid substitute for phosgene, which is a gas and diphosgene, which is a liquid. Triphosgene is stable up to 200 °C. Triphosge ...

pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom . It is a highly flammable, weak ...

). The tertiary alcohol group was

acetylated : In chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply ''acetates''. Deacetylation is the opposite reacti ...

in 5.6 and in the final step the carbonate group was opened by reaction with

phenyllithium Phenyllithium is an organometallic agent with the empirical formula . 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. Crystalline phenyl ...

to the hydroxyester 5.7. Prior to tail addition the TES protective group was removed in 5.8 (

hydrogen fluoride Hydrogen fluoride (fluorane) is an Inorganic chemistry, inorganic compound with chemical formula . It is a very poisonous, colorless gas or liquid that dissolves in water to yield hydrofluoric acid. It is the principal industrial source of fluori ...

) and replaced by a TROC (trichloroethyl carbonate, TROCCl ) group in 5.9. The C13 alcohol protective group was removed in 5.10 (

TASF The TASF reagent or tris(dimethylamino)sulfonium difluorotrimethylsilicate is a reagent in organic chemistry with structural formula (CH3)2N)3Ssup>+ 2Si(CH3)3sup>−. It is an anhydrous source of fluoride and is used to cleave silyl ether prote ...

) enabling the tail addition of

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 is a lithiated organosilicon compound with the formula . It is commonly abbreviated as LiHMDS or Li(HMDS) (lithium hexamethyldisilazide - a reference to its conjugate acid HMDS) and is primarily used as a strong ...

. The synthesis was completed with TROC removal (

zinc Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...

acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main compone ...

) to taxol 5.13.

External links

Kuwajima Taxol Synthesis @ SynArchive.com

References

{{reflist Total synthesis Taxanes