The longest two organic synthetic routes in history

- Jul 17, 2018-

Who is the "most powerful cow" of organic synthesis in the world today? There is no doubt that it is nature. Chemists have been trying to mimic the magical power of nature to synthesize complex molecules, and countless teams are hoping to get a full synthetic route to a natural product, especially in the pharmaceutical industry. However, the total synthetic route of natural products tends to be very long, and due to their high price and unfriendly environment, these synthetic compounds are far less widely used commercially than those readily available compounds.


However, these complex natural product molecules sometimes have extremely miraculous medicinal effects, and common compounds are often incomparable. For example, the highly effective anticancer drug Taxol was first extracted from the bark of the Pacific cedar (Taxus brevifolia) in the 1960s, but due to its low content, it is necessary to cut down 6 trees per 0.5 g of paclitaxel. This means that hundreds of large trees are cut off for drug experiments.


In order to protect the yew tree, researchers in the synthetic world began to fully synthesize paclitaxel. In 1994, the two research groups completed the complete synthesis of the compound, and the two epic synthetic routes included 40 steps. The semi-synthetic route that was later developed finally allowed the compound to be produced commercially. A compound called 10-deacetylbaccatin (10-DAB) is used, which is highly contained in the branches and leaves of the genus Taxus baccata, and can avoid the whole plant. The destruction. From the 10-DAB, Robert Holton of Florida State University designed a four-step synthetic route that included a reaction with β-lactams, which itself required several steps to prepare. In 1994, paclitaxel producer Bristol-Myers Squibb purchased this semi-synthetic route and made paclitaxel a "heavy" new drug. In 2002, they switched to plant cell fermentation to produce paclitaxel directly.

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Not every complex natural product can be synthesized like paclitaxel. This article will present the synthetic routes of the two most complex natural products to date. These two natural products are now marketed as drugs and are found in marine life. Whether you look at these reactions from a critical point of view, or simply appreciate them from an artistic point of view, it is undeniable that they all have a very special charm.


Eribulin (Ai Riblin, trade name Halaven)


Halichondrin B can effectively kill cancer cells in mice, and 80 skins can be effective. But for the compositor, it is an uncompromising "devil", which starts with its large-loop polyketone structure with 32 stereocenters. This "evil" incomparable structure means it has as many as 4 billion isomers - but only one has anti-cancer activity (small narration: can you still make people happy to move bricks?).

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In the 1980s, halichaxin B was found in a variety of natural sponge species, but 400 mg of nephrostaside B was extracted per ton of sponge, and at least 10 g was required for clinical development alone. It is unrealistic to extract the soft-spongein B from the sponge, but its full synthesis looks like “unreliable” from the sponge, but the Yoshito Kishi team at Harvard University accepted the challenge. Frank Fang, one of the team members, recalled that the Nozaki-Hiyama-Kishi (NHK) coupling reaction they used in total synthesis was critical throughout the route. “Another feature that impressed me was the importance of crystallization of the intermediates,” Fang added. By recrystallization, not only can the purification step be simplified, but expensive and time consuming column chromatography can also be avoided.

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In 1992, they reported on the results of this study, using several NHK coupling reactions to form a C-C bond between the polyfunctional vinyl halide and the aldehyde. This seemingly clueless synthetic route lasts 47 steps. At this time, Eisai and Kishi collaborated to study the structure-activity relationship of halichaxin B. In studying the intermediates of halichondrin B, the researchers found that a macrocyclic intermediate was very active. Through a series of structural improvements, eribulin (Eisai has its trade name Halaven) finally stands out, its synthesis steps are relatively simple, and the stereocenter "only" only 19, which also makes the number of isomers of the compound from 40 Yi Rui was reduced to "only" 16,384.


Fang joined Eisai in 1998, when Eisai was ready to further optimize the synthesis of eribulin and planned to synthesize eribulin through three segments. Fang once again used NHK reaction and recrystallization for the synthesis of the C14-C26 fragment, which finally reached the scale of production of kilograms. Eribulin's final commercial synthetic route was 62 steps, which also pushed up the price of the drug to some extent. In the UK, a 21-day Halaven treatment costs up to £2,000. Fang's team is also looking for ways to optimize costs and reduce costs. Recently, they added 7 steps to the C14-C26 fragment synthesis route to remove the chromatographic process. This change can reduce cost and waste generation by 80%.

(Angew. Chem., Int. Ed., 2015, 54, 5108, DOI: 10.1002/anie.201501143).

Trabectedin (Qubetinidine, trade name Yondelis)


Although scientists first reported in 1969 that Caribbean sea squirt extract may prolong the lifespan of cancer patients, it was not until 38 years later that the effect was truly realized. The structure of the active compound, ecteinascidins, was determined many years later, and chemists discovered a unique structure containing two or three tetrahydroisoquinoline rings and a thioether bond. The 10-member lactone ring.



Kenneth Rinehart of the University of Illinois at Urbana-Champaign collected the sea squirt while diving in the West Indies, obtained the patent for the compound and licensed it to PharmaMar, Spain. To produce enough lead compound, trabectedin, for clinical development, PharmaMar raised 250 tons of Ecteinascidia turbinata (an ascidian) to extract this compound. However, complex separation and purification processes result in very low production of trabectedin, with less than one gram of product per ton of E. turbinata. Aware of the difficulty of the process, Rinehart collaborated with Harvard's synthetic big cow E. J. Corey and asked him to establish a synthetic route.

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Corey's research team completed this synthetic route in 1996, including the integration of four fragments, all synthetic routes including more than 40 steps, with a total yield of less than 2%. A fragment located at the center of the molecule forms a fused piperazine ring linking the first two fragments. Researchers at Harvard University used the Mannich reaction to obtain the skeleton structure of the compound, and then constructed a 10-membered lactone bridge and created a quinone methide on the side of the corresponding tetrahydroisoquinoline (external olefin conjugated ring). ), the sulfur atom at the end of the chain can attack the ring from the other side. “This is great, there is no chemical improvement, there will never be such a product on the market,” said Carmen Cuevas, director of research and development at PharmaMar.


In 1999, Cuevas began the production of the antibiotic safracin B using the bio-fermentation process of Pseudomonas fluorescens. The molecule possesses many fused ring structures of ectoin, including fused piperazine, which gives the Harvard team a more concise alternative to some of the synthetic pathways created by the Harvard team. However, it does not contain a 10-membered ring and is very unstable. Cuevas found that adding potassium cyanide at the end of the fermentation would resolve the instability of the reaction and result in a more stable cyanosafracin B molecule. "The pH of the reaction is around 4, which means that you are surrounded by hydrogen cyanide," Cuevas said. "It's hard to achieve because no one wants to work under such conditions."


Under the pressure of Phase III clinical trials, Cuevas and two other PharmaMar scientists needed to prepare a sufficient amount of compounds, and they began to improve Corey's synthetic steps. The three of them had to overcome a seemingly small, but actually very challenging, structural difference - the amine on cyanosafracin B, while the full synthesis required alcohol. In the months before the expansion with the partners, they continually modified the protection-based strategy and finally succeeded. At the end of 2001, the method was still industrialized. “The speed of the process is a bit crazy,” Cuevas recalls. “I don’t know if we can successfully replicate this process in the future.”

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Yondelis was first approved in the European Union in 2007 for the treatment of soft tissue sarcomas. There are currently 80 countries that are selling the drug, with annual global revenues exceeding $100 million. Although some reaction steps have been improved today, such as avoiding chromatographic purification and separation of some intermediates, the route still contains 18 steps.

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