Antibiotics discovered half a century ago in the soil of a Cameroon volcano have finally been processed by Japanese researchers, giving medical scientists a new potential drug to fight infection. In 1974, German chemist Axel Zeck and his Turkish colleague Mithat Mardin demonstrated the existence of red pigments produced by bacteria. Streptomyces arenas, They have antimicrobial properties, making them an attractive material for pharmacologists.

Synthesis of useful amounts of potentially useful compounds known as β- and γ-naphthocyclones has proven challenging. Although the complexity of naphthocyclinones makes them difficult to create without various byproducts emerging, finding the necessary chemical reactions often requires some trial and error.

Researchers at the Tokyo Institute of Science were only able to do this using an approach now known as retrosynthetic analysis. As you might guess from the name, this involves working backwards from the target molecule to identify its basic building blocks. This is like breaking a complex machine into component parts that are easier to understand and assemble.

The team started with β-naphthocyclone because it can be considered a type of γ-naphthocyclone. As with many large molecules, the combination of simpler molecular units served as the starting point for creating a compound.

The bridge between the two units is a complex molecule called a bicyclo.[3.2.1]Moving the chemical into the ideal position without changing other ingredients or creating a completely different product is easier said than done, says octadienone. By following retrosynthesis recipes and using a series of advanced chemical techniques, researchers have found a way that allows them to precisely position the pieces and hold them together in a way that does not affect their function.

The moment of truth came when comparing the exact three-dimensional arrangement of atoms (or circular dichroism spectra in scientific terms) of the synthesized compounds with those created by nature in the volcano.

“The circular dichroism spectra of our synthesized compounds were the same as the spectra of the natural ones, meaning that the absolute configuration of the synthetic and natural molecules was the same,” says chemist Yoshio Ando of the Tokyo Institute of Science.

These methods eventually allowed the researchers to synthesize β-naphthocyclone in at least 70 percent yield (that is, 70 percent of the maximum amount expected given the starting materials). They then used another chemical process, oxidative lactonization, to produce γ-naphthocyclone in 87 percent yield. The two compounds are similar, but γ-naphthocyclone has some additional properties.

Laboratory synthesis of antibiotics could lead to their production in large quantities for medical and research purposes: for example, there is no need to regularly return to a volcano. Moreover, the researchers believe that the carefully calibrated approaches they used here can also be used in future studies, especially for the synthesis of other compounds with similar structures.

“Further efforts in this direction are already underway in our laboratory,” says Ando. The study was published on: Angewandte Chemie International Edition.