Molecular structure of paclitaxel.Crystal structure of paclitaxel.
Paclitaxel total synthesis in organic chemistry is a major ongoing research effort in the total synthesis of paclitaxel (Taxol).[1] 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 (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 and an amide tail. The core rings are conveniently called (from left to right) ring A (a cyclohexene), ring B (a cyclooctane), ring C (a cyclohexane) and ring D (an oxetane).
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 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 (the european yew). In 1990 Bristol-Myers Squibb 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 dollars.
Total synthesis
Taxol numbering schemeTaxol synthesis routes showing the precursors used by each of them.
The total synthesis of taxol is called one of the most hotly contested of the 1990s [2] 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.
Nakada Taxol total synthesis - year: 2015, formal synthesis to a Takahashi intermediate [15]
Baran Taxol total synthesis - year: 2020, total synthesis via a two-phase divergent synthetic approach.[16]
Li Taxol total synthesis - year: 2021, total synthesis via B ring closure by forming C1–C2 bond.[17]
Ongoing research efforts are directed at the synthesis of taxadiene and taxadienone intermediates. The synthesis of related taxanes decinnamoyltaxinine E and taxabaccatin III has been reported [18]
Semisynthesis
The commercial semisynthesis (by Bristol-Myers Squibb) of paclitaxel starting from 10-deacetylbaccatin III (isolated from the European yew) is based on tail addition of the so-called Ojima lactam to its free hydroxyl group:
Semisynthesis of taxol from 10-deacetylbaccatin and (3R,4S)-3-triethylsilanyloxy-4-phenyl-N-Boc-2-azetidinone
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, or propyl or pentyl (among others) whereas in paclitaxel it is an explicit phenyl group. The semisynthesis consists of conversion of the amide group to an amine with Schwartz's reagent through an imine followed by acidic workup and a benzoylation.
In the production process Michigan 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.[19]
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 diphosphate2[20] which is a dimer of geraniol1. This compound already contains all the required 20 carbon atoms for the paclitaxel skeleton. More ring closing through intermediate 3 (taxadiene) 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 and a much better job activating a hydrocarbon skeleton with oxygen substituents for which cytochrome P450 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 in 2011.[21]
References and notes
↑ Note that the original publications about the total synthesis use the name "taxol", which used to be the generic name before it was accepted as a trademark in 1992.
↑ Robert A. Holton; Carmen Somoza; Hyeong Baik Kim; Feng Liang; Ronald J. Biediger; P. Douglas Boatman; Mitsuru Shindo; Chase C. Smith; Soekchan Kim; Hossain Nadizadeh; Yukio Suzuki; Chunlin Tao; Phong Vu; Suhan Tang; Pingsheng Zhang; Krishna K. Murthi; Lisa N. Gentile; Jyanwei H. Liu (1994). "First total synthesis of taxol. 1. Functionalization of the B ring". J. Am. Chem. Soc.116 (4): 1597–1598. doi:10.1021/ja00083a066.
↑ Robert A. Holton; Hyeong-Baik Kim; Carmen Somoza; Feng Liang; Ronald J. Biediger; P. Douglas Boatman; Mitsuru Shindo; Chase C. Smith; Soekchan Kim; Hossain Nadizadeh; Yukio Suzuki; Chunlin Tao; Phong Vu; Suhan Tang; Pingsheng Zhang; Krishna K. Murthi; Lisa N. Gentile; Jyanwei H. Liu (1994). "First Total Synthesis of Taxol. 2. Completion of the C and D Rings". J. Am. Chem. Soc. 116 (4): 1599–1600. doi:10.1021/ja00083a067.
↑ Paul A. Wender, Neil F. Badham, Simon P. Conway, Paul E. Floreancig, Timothy E. Glass, Christian Gränicher, Jonathan B. Houze, Jan Jänichen, Daesung Lee, Daniel G. Marquess, Paul L. McGrane, Wei Meng, Thomas P. Mucciaro, Michel Mühlebach, Michael G. Natchus, Holger Paulsen, David B. Rawlins, Jeffrey Satkofsky, Anthony J. Shuker, James C. Sutton, Richard E. Taylor, and Katsuhiko Tomooka (1997) "The Pinene Path to Taxanes. 5. Stereocontrolled Synthesis of a Versatile Taxane Precursor" J. Am. Chem. Soc.119 (11), 2755-2756 (Communication) doi:10.1021/ja9635387
↑ Paul A. Wender, Neil F. Badham, Simon P. Conway, Paul E. Floreancig, Timothy E. Glass, Jonathan B. Houze, Nancy E. Krauss, Daesung Lee, Daniel G. Marquess, Paul L. McGrane, Wei Meng, Michael G. Natchus, Anthony J. Shuker, James C. Sutton, and Richard E. Taylor (1997) "The Pinene Path to Taxanes. 6. A Concise Stereocontrolled Synthesis of Taxol" J. Am. Chem. Soc.119 (11), 2757-2758 (Communication) doi:10.1021/ja963539z
↑ Koichiro Morihira, Ryoma Hara, Shigeru Kawahara, Toshiyuki Nishimori, Nobuhito Nakamura, Hiroyuki Kusama, and Isao Kuwajima (1998) "Enantioselective Total Synthesis of Taxol" J. Am. Chem. Soc.120 (49), 12980-12981 (Communication) doi:10.1021/ja9824932
↑ Hiroyuki Kusama, Ryoma Hara, Shigeru Kawahara, Toshiyuki Nishimori, Hajime Kashima, Nobuhito Nakamura, Koichiro Morihira, and Isao Kuwajima (2000) "Enantioselective Total Synthesis of (−)-Taxol" J. Am. Chem. Soc.122 (16) 3811-3820. doi:10.1021/ja9939439
↑ Isamu Shiina, Hayato Iwadare, Hiroki Sakoh, Masatoshi Hasegawa, Yu-ichirou Tani, and Teruaki Mukaiyama (1998) "A New Method for the Synthesis of Baccatin III" Chemistry Letters27 (1), 1-2 doi:10.1246/cl.1998.1
↑ Takayuki Doi, Shinichiro Fuse, Shigeru Miyamoto, Kazuoki Nakai, Daisuke Sasuga and Takashi Takahashi (2006) "A Formal Total Synthesis of Taxol Aided by an Automated Synthesizer" Chemistry: An Asian Journal1 (3), 370-383. doi:10.1002/asia.200600156
↑ Keisuke Fukaya, Yuta Tanaka, Ayako C. Sato, Keisuke Kodama, Hirohisa Yamazaki, Takeru Ishimoto, Yasuyoshi Nozaki, Yuki M. Iwaki, Yohei Yuki, Kentaro Umei, Tomoya Sugai, Yu Yamaguchi, Ami Watanabe, Takeshi Oishi, Takaaki Sato, and Noritaka Chida (2015) "Synthesis of Paclitaxel. 1. Synthesis of the ABC Ring of Paclitaxel by SmI2-Mediated Cyclization" Organic Letters17 (11), 2570-2573 doi:10.1021/acs.orglett.5b01173
↑ Keisuke Fukaya, Keisuke Kodama, Yuta Tanaka, Hirohisa Yamazaki, Tomoya Sugai, Yu Yamaguchi, Ami Watanabe, Takeshi Oishi, Takaaki Sato, and Noritaka Chida (2015) "Synthesis of Paclitaxel. 2. Construction of the ABCD Ring and Formal Synthesis" Organic Letters17 (11), 2574-2577 doi:10.1021/acs.orglett.5b01174
↑ Sho Hirai, Masayuki Utsugi, Mitsuhiro Iwamoto, Masahisa Nakada (2015), "Formal Total Synthesis of (−)-Taxol through Pd-Catalyzed Eight-Membered Carbocyclic Ring Formation" Chemistry: A European Journal21 (1), 355–359. doi:10.1002/chem.201404295
↑ Yuzuru Kanda, Hugh Nakamura, Shigenobu Umemiya, Ravi Kumar Puthukanoori, Venkata Ramana Murthy Appala, Gopi Krishna Gaddamanugu, Bheema Rao Paraselli, and Phil Baran (2020), "Two-Phase Synthesis of Taxol" doi:10.1021/jacs.0c03592
↑ Changxia Yuan, Yehua Jin, Nathan C. Wilde, Phil S. Baran (2016) "Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes" Angew. Chem. Int. Ed.55 (29), 8280-8284 doi:10.1002/anie.201602235
↑ Bruce Ganem and Roland R. Franke (2007) "Paclitaxel from Primary Taxanes: A Perspective on Creative Invention in Organozirconium Chemistry" J. Org. Chem.72 (11), 3981-3987. doi:10.1021/jo070129s
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 intravenous injection. There is also an albumin-bound formulation.
Semisynthesis, or partial chemical synthesis, is a type of chemical synthesis that uses chemical compounds isolated from natural sources as the starting materials to produce novel compounds with distinct chemical and medicinal properties. The novel compounds generally have a high molecular weight or a complex molecular structure, more so than those produced by total synthesis from simple starting materials. Semisynthesis is a means of preparing many medicines more cheaply than by total synthesis since fewer chemical steps are necessary.
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 it from semisynthesis. Syntheses may sometimes conclude at a precursor with further known synthetic pathways to a target molecule, in which case it is known as a formal synthesis. Total synthesis target molecules can be natural products, medicinally-important active ingredients, known intermediates, or molecules of theoretical interest. Total synthesis targets can also be organometallic or inorganic, though these are rarely encountered. Total synthesis projects often require a wide diversity of reactions and reagents, and subsequently requires broad chemical knowledge and training to be successful.
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 general subject of organic synthesis, there are many different types of synthetic routes that can be completed including total synthesis, stereoselective synthesis, automated synthesis, and many more. Additionally, in understanding organic synthesis it is necessary to be familiar with the methodology, techniques, and applications of the subject.
The chiral pool is a "collection of abundant enantiopure building blocks provided by nature" used in synthesis. In other words, a chiral pool would be a large quantity of common organic enantiomers. Contributors to the chiral pool are amino acids, sugars, and terpenes. Their use improves the efficiency of total synthesis. Not only does the chiral pool contribute a premade carbon skeleton, their chirality is usually preserved in the remainder of the reaction sequence.
The Nicolaou Taxol total synthesis, published by K. C. Nicolaou and his group in 1994 concerns the total synthesis of taxol. Taxol 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.
Ring-closing metathesis (RCM) is a widely used variation of olefin metathesis in organic chemistry for the synthesis of various unsaturated rings via the intramolecular metathesis of two terminal alkenes, which forms the cycloalkene as the E- or Z- isomers and volatile ethylene.
The Wieland–Miescher ketone is a racemic bicyclic diketone (enedione) and is a versatile synthon which has so far been employed in the total synthesis of more than 50 natural products, predominantly sesquiterpenoids, diterpenes and steroids possessing possible biological properties including anticancer, antimicrobial, antiviral, antineurodegenerative and immunomodulatory activities. The reagent is named after two chemists from Ciba Geigy, Karl Miescher and Peter Wieland. Examples of syntheses performed using the optically active enantiomer of this diketone as a starting material are that of ancistrofuran and the Danishefsky total synthesis of Taxol.
The Danishefsky Taxol total synthesis in organic chemistry is an important third Taxol synthesis published by the group of Samuel Danishefsky in 1996 two years after the first two efforts described in the Holton Taxol total synthesis and the Nicolaou Taxol total synthesis. Combined they provide a good insight in the application of organic chemistry in total synthesis.
Taxanes are a class of diterpenes. They were originally identified from plants of the genus Taxus (yews), and feature a taxadiene core. Paclitaxel (Taxol) and docetaxel (Taxotere) are widely used as chemotherapy agents. Cabazitaxel was FDA approved to treat hormone-refractory prostate cancer.
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.
Epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials, epothilones have better efficacy and milder adverse effects than taxanes.
Wender Taxol total synthesis in organic chemistry describes a Taxol total synthesis by the group of Paul Wender at Stanford University published in 1997. This synthesis has much in common with the Holton Taxol total synthesis in that it is a linear synthesis starting from a naturally occurring compound with ring construction in the order A,B,C,D. The Wender effort is shorter by approximately 10 steps.
The Kuwajima Taxol total synthesis by the group of Isao Kuwajima of the Tokyo Institute of Technology is one of several efforts in taxol total synthesis published in the 1990s. The total synthesis of Taxol is considered a landmark in organic synthesis.
The 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.
Baccatin III is an isolate from the yew tree. Baccatin III is a precursor to the anti-cancer drug paclitaxel (Taxol).
An oxaziridine is an organic molecule that features a three-membered heterocycle containing oxygen, nitrogen, and carbon. In their largest application, oxaziridines are intermediates in the industrial production of hydrazine. Oxaziridine derivatives are also used as specialized reagents in organic chemistry for a variety of oxidations, including alpha hydroxylation of enolates, epoxidation and aziridination of olefins, and other heteroatom transfer reactions. Oxaziridines also serve as precursors to nitrones and participate in [3+2] cycloadditions with various heterocumulenes to form substituted five-membered heterocycles. Chiral oxaziridine derivatives effect asymmetric oxygen transfer to prochiral enolates as well as other substrates. Some oxaziridines also have the property of a high barrier to inversion of the nitrogen, allowing for the possibility of chirality at the nitrogen center.
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.
Biomimetic synthesis is an area of organic chemical synthesis that is specifically biologically inspired. The term encompasses both the testing of a "biogenetic hypothesis" through execution of a series of reactions designed to parallel the proposed biosynthesis, as well as programs of study where a synthetic reaction or reactions aimed at a desired synthetic goal are designed to mimic one or more known enzymic transformations of an established biosynthetic pathway. The earliest generally cited example of a biomimetic synthesis is Sir Robert Robinson's organic synthesis of the alkaloid tropinone.
Taxadienone is an organic compound and a taxane. The compound is of some academic interest as a potential precursor to Taxol, in important anti-cancer drug, in a commercially viable process. A total synthesis of taxadienone was reported in 2012 together with its conversion to the next Taxol precursor taxadiene. A multigram synthetic method was reported in 2015.
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