Natural products are chemical compounds that occur in nature and often provide us with inspiration or a blueprint for potential medicines. aspirin and penicillins were originally isolated from moulds in 1928, and are examples of classic examples. It can be difficult to make these compounds in a lab. A new synthetic route to a group of spirocyclic compounds has been published by chemists in Japan, removing a roadblock for their use as potential drug candidates.
Spirocyclic compounds are made up of two or more rings that are joined by a single atom. They can be one or more non-carbon atoms. These compounds can be found in plants and marine sponges.
The compound is inherently threedimensional thanks to the spiral skeleton. Histrionicotoxin is a family of spirocyclic chemical compounds that has been isolated from poison dart frog. All are built on a spirocyclic skeleton called 1-azaspiroundecane, which is common to other alkaloids.
One of the rings has a single nitrogen atom. There are potential target drugs for HTX compounds. The synthesis is lengthy and inefficient because all laboratories follow multistep processes.
A one-step approach to making a skeleton has been developed by researchers. They used this method to make two HTX compounds, including HTX-283A, which is a neurotoxin that does not compete. The research team's method was based on a successful reaction they had done before.
The method used linear starting materials and a mercury-based catalyst, and proceeded through a 5-membered ring as an intermediate. The previously tried-and-true reaction produced two linear by-products instead of generating any spirocycle. The team determined that the reduced reactivity in this substrate was preventing the cyclization step.
Water contaminants were hydrating the compound to produce the by-products. The bulky Boc protecting group was used to block the reactions from occurring at the nitrogen atom. The reaction was less inhibited by changing it to a smaller protecting group.
The simple linear substrates are cyclized in a single step, Hg( OTf) 2 -catalysed reaction and further steps produce the final spirocyclic products. Researchers worked to improve the reaction. They increased the yield by changing the size of other side groups, adjusting the catalyst loading, changing the solvent to acetonitrile, and using anhydrous conditions.
The team completed the synthesis of HTX compounds with a single step method. They will use this method to make other HTX analogues and natural products and the reaction might help researchers to make new pharmaceuticals in the future. One-Step Synthesis of the 1-Azaspiro[5.5]undecane Skeleton Characteristic of Histrionicotoxin Alkaloids from Linear Substrates via Hg(OTf) 2-Catalyzed Cycloisomerization is a reference.
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