Paclitaxel total synthesis in

organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...

is a major ongoing research effort in the

total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes ...

paclitaxel Paclitaxel (PTX), sold under the brand name Taxol among others, is a chemotherapy medication used to treat a number of types of cancer. This includes ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer ...

(Taxol). This

diterpenoid Diterpenes are a class of chemical compounds composed of four isoprene units, often with the molecular formula C20H32. They are biosynthesized by plants, animals and fungi via the HMG-CoA reductase pathway, with geranylgeranyl pyrophosphate being ...

is an important

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...

in the treatment of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

but, also expensive because the compound is harvested from a scarce resource, namely the

Pacific yew ''Taxus brevifolia'', the Pacific yew or western yew, is a species of tree in the yew family Taxaceae native to the Pacific Northwest of North America. It is a small evergreen conifer, thriving in moisture and otherwise tending to take the form o ...

(''Taxus brevifolia''). Not only is the synthetic reproduction of the compound itself of great commercial and scientific importance, but it also opens the way to paclitaxel derivatives not found in nature but with greater potential. The paclitaxel molecule consists of a tetracyclic core called

baccatin III Baccatin III is an isolate from the yew tree (Genera ''Taxus''). Baccatin III is a precursor to the anti-cancer drug paclitaxel (Taxol). In 2014, researchers reported introduction and expression of the endophytic fungal gene responsible for synt ...

and an

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

tail. The core rings are conveniently called (from left to right) ring A (a

cyclohexene Cyclohexene is a hydrocarbon with the formula C6H10. This cycloalkene is a colorless liquid with a sharp smell. It is an intermediate in various industrial processes. Cyclohexene is not very stable upon long term storage with exposure to light an ...

), ring B (a

cyclooctane Cyclooctane is a cycloalkane with the molecular formula (CH2)8. It is a simple colourless hydrocarbon, but it is often a reference compound for saturated eight-membered ring compounds in general. Cyclooctane has a camphoraceous odor. Conformat ...

), ring C (a

cyclohexane Cyclohexane is a cycloalkane with the molecular formula . Cyclohexane is non-polar. Cyclohexane is a colorless, flammable liquid with a distinctive detergent-like odor, reminiscent of cleaning products (in which it is sometimes used). Cyclohexan ...

) and ring D (an

oxetane Oxetane, or 1,3-propylene oxide, is a 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 compound containing ...

). The paclitaxel drug development process took over 40 years. The anti-tumor activity of a bark extract of the Pacific yew tree was discovered in 1963 as a follow up of a US government plant screening program already in existence 20 years before that. The active substance responsible for the anti-tumor activity was discovered in 1969 and structure elucidation was completed in 1971. Robert A. Holton of

Florida State University Florida State University (FSU) is a public research university in Tallahassee, Florida. It is a senior member of the State University System of Florida. Founded in 1851, it is located on the oldest continuous site of higher education in the st ...

succeeded in the total synthesis of paclitaxel in 1994, a project that he had started in 1982. In 1989 Holton had also developed a semisynthetic route to paclitaxel starting from 10-deacetylbaccatin III. This compound is a biosynthetic precursor and is found in larger quantities than paclitaxel itself in ''

Taxus baccata ''Taxus baccata'' is a species of evergreen tree in the family Taxaceae, native to western, central and southern Europe (including Britain and Ireland), northwest Africa, northern Iran, and southwest Asia.Rushforth, K. (1999). ''Trees of Britain ...

'' (the european yew). In 1990

Bristol-Myers Squibb The Bristol Myers Squibb Company (BMS) is an American multinational pharmaceutical company. Headquartered in New York City, BMS is one of the world's largest pharmaceutical companies and consistently ranks on the ''Fortune'' 500 list of the lar ...

bought a licence to the patent for this process which in the years to follow earned Florida State University and Holton (with a 40% take) over 200 million

US dollar The United States dollar (symbol: $; code: USD; also abbreviated US$ or U.S. Dollar, to distinguish it from other dollar-denominated currencies; referred to as the dollar, U.S. dollar, American dollar, or colloquially buck) is the official ...

Total synthesis

The total synthesis of taxol is called one of the most hotly contested of the 1990s with around 30 competing research groups by 1992. The number of research groups actually having reported a total synthesis currently stands at 11 with the Holton group (article first accepted for publication) and the Nicolaou group (article first published) first and second in what is called a photo finish. Some of the efforts are truly synthetic but in others a precursor molecule found in nature is included. The key data are collected below. What all strategies have in common is synthesis of the baccatin molecule followed by last stage addition of the tail, a process (except for one) based on the

Ojima lactam Ojima may refer to: *Ojima (surname), a Japanese surname *Ojima, Gunma, a town merged into the city of Ōta, Gunma Prefecture, Japan *Ojima Station, a railway station in Kōtō, Tokyo, Japan *Higashi-ojima Station, a railway station in Kōtō, Toky ...

. # Holton Taxol total synthesis - year: 1994 - precursor:

Patchoulol Patchoulol or patchouli alcohol (C15H26O) is a sesquiterpene alcohol found in patchouli. Patchouli oil is an important material in perfumery. The (−)- optical isomer is one of the organic compounds responsible for the typical patchouli scent. Pa ...

strategy:

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, ...

AB then C then D - references: see related article # Nicolaou Taxol total synthesis - year: 1994 - precursor:

Mucic acid Mucic acid, C6H10O8 or HOOC-(CHOH)4-COOH (also known as galactaric or meso-galactaric acid) is an aldaric acid obtained by nitric acid oxidation of galactose or galactose-containing compounds such as lactose, dulcite, quercite, and most varietie ...

strategy:

convergent 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, ...

A and C merge to ABC then D - references: see related article # Danishefsky Taxol total synthesis - year: 1996 - precursor: Wieland-Miescher ketone strategy:

C merges with D then with A merges to ABCD - references: See related article #

Wender Taxol total synthesis Wender Taxol total synthesis in organic chemistry describes a Taxol total synthesis (one of six to date) by the group of Paul Wender at Stanford University published in 1997.''The Pinene Path to Taxanes. 6. A Concise Stereocontrolled Synthesis o ...

- year: 1997 - precursor:

Pinene Pinene is a collection of unsaturated bicyclic monoterpenes. Two geometric isomers of pinene are found in nature, α-pinene and β-pinene. Both are chiral. As the name suggests, pinenes are found in pines. Specifically, pinene is the major compo ...

strategy:

AB then C then D - references: #

Kuwajima Taxol total synthesis 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 synth ...

I. Kuwajima, - year: 1998 - precursor: synthetic building blocks strategy:

A then B then C then D # Mukaiyama Taxol total synthesis - year: 1998 - Precursor:

L-serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

strategy: linear synthesis B, then C, then A then D. References: see related article. #

Takahashi Taxol total synthesis The Takahashi Taxol total synthesis published by Takashi Takahashi in 2006 is one of several methods in taxol total synthesis.''A Formal Total Synthesis of Taxol Aided by an Automated Synthesizer'' Takayuki Doi, Shinichiro Fuse, Shigeru Miyamoto, ...

- year: 2006 - Precursor:

geraniol Geraniol is a monoterpenoid and an alcohol. It is the primary component of citronella oil and is a primary component of rose oil, palmarosa oil. It is a colorless oil, although commercial samples can appear yellow. It has low solubility in water ...

strategy:

A and C merge to ABC then D # Sato-Chida Taxol total synthesis - year: 2015, formal synthesis to a Takahashi intermediate # Nakada Taxol total synthesis - year: 2015, formal synthesis to a Takahashi intermediate # Baran Taxol total synthesis - year: 2020,

via a two-phase divergent synthetic approach. # Li Taxol total synthesis - year: 2021, total synthesis via B ring closure by forming C1–C2 bond. Ongoing research efforts are directed at the synthesis of

taxadiene Taxadiene (taxa-4,11-diene) is a diterpene. Taxadiene is the first committed intermediate in the synthesis of taxol. Six hydroxylation reactions, and a few others, are needed to convert taxadiene to baccatin III. Enzymatically, taxadiene is prod ...

and taxadienone intermediates. The synthesis of related taxanes ''decinnamoyltaxinine E'' and ''taxabaccatin III'' has been reported

Semisynthesis

The commercial

semisynthesis Semisynthesis, or partial chemical synthesis, is a type of chemical synthesis that uses chemical compounds isolated from natural sources (such as microbial cell cultures or plant material) as the starting materials to produce novel compounds with ...

(by

) of paclitaxel starting from 10-deacetylbaccatin III (isolated from the European yew) is based on tail addition of the so-called

to its free hydroxyl group: Original semi-synthesis of taxol

Another commercial semisynthesis (by the company ''Natural Pharmaceuticals'') relies on the isolation of a group of paclitaxel derivatives isolated from primary ornamental taxanes. These derivatives have the same skeleton as paclitaxel except for the organic residue R of the terminal tail amide group which can be

phenyl In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...

, or

propyl In organic chemistry, propyl is a three-carbon alkyl substituent with chemical formula for the linear form. This substituent form is obtained by removing one hydrogen atom attached to the terminal carbon of propane. A propyl substituent is often ...

pentyl Pentyl is a five-carbon alkyl group or substituent with chemical formula -C5H11. It is the substituent form of the alkane pentane. In older literature, the common non-systematic name amyl was often used for the pentyl group. Conversely, the name ...

(among others) whereas in paclitaxel it is an explicit

group. The semisynthesis consists of conversion of the amide group to an

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...

with

Schwartz's reagent Schwartz's reagent is the common name for the organozirconium compound with the formula (C5H5)2ZrHCl, sometimes called zirconocene hydrochloride or zirconocene chloride hydride, and is named after Jeffrey Schwartz, a chemistry professor at Prince ...

through an

imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...

followed by acidic workup and a benzoylation. : In the production process

Michigan Michigan () is a state in the Great Lakes region of the upper Midwestern United States. With a population of nearly 10.12 million and an area of nearly , Michigan is the 10th-largest state by population, the 11th-largest by area, and the ...

grown yews which mature in 8 years are periodically topped and dried. This material is shipped to Mexico for a first extraction step (10% paclitaxel content) and then to Canada for further purification to 95% purity. The semisynthesis to final product takes place in China.

Biosynthesis

: The biosynthetic pathway to paclitaxel has been investigated and consists of approximately 20 enzymatic steps. The complete scheme is still unavailable. The segments that are known are very different from the synthetic pathways tried thus far (''Scheme 1''). The starting compound is geranylgeranyl

diphosphate In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among othe ...

2 which is a dimer of

1. This compound already contains all the required 20 carbon atoms for the paclitaxel skeleton. More ring closing through intermediate 3 (

) leads to taxusin 4. The two main reasons why this type of synthesis is not feasible in the laboratory is that nature does a much better job controlling

stereochemistry Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...

and a much better job activating a hydrocarbon skeleton with oxygen substituents for which

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

is responsible in some of the oxygenations. Intermediate 5 is called 10-deacetylbaccatin III. A biochemical kilogram-scale production of taxadiene was reported using genetically engineered ''

E. coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...

'' in 2011.

References and notes

{{reflist, 3

External links

Paclitaxel Total Syntheses @ SynArchive.com

Taxolog for Taxol research
founded by Holto * The complete Taxol story from ''

Chemical & Engineering News ''Chemical & Engineering News'' (''C&EN'') is a weekly news magazine published by the American Chemical Society, providing professional and technical news and analysis in the fields of chemistry and chemical engineering.Article

Total synthesis Taxanes