Nature Chem.: New Fluoro Organic Molecular Synthesis Strategy Expands Drug development
Although we often see some negative news about fluoride recently, such as the environmental pollution caused by it and the potential danger of fluorinated polymers to the human body (related reading: The US FDA prohibits the use of three perfluorinated compounds in food packaging materials). However, there is actually no need to talk about "fluorine" discoloration. Fluorine is a Electronegativity atom in the periodic table of elements, and it is widely used in organic and Medicinal chemistry. In fact, replacing hydrogen with fluorine often improves the biological activity of drugs, and due to the strong carbon fluorine bonds, it is more tolerant of the metabolic chemical environment in the body. For this reason, many chemists are enthusiastic about manufacturing fluorinated derivatives of drugs. However, for certain organic compounds, it is difficult to obtain their functionalized fluorinated derivatives.
Recently, chemists Jakub Saadi and Helma Wennemers of the Organic Chemistry Laboratory of the ETH Zurich in Switzerland have developed a universal bionic method, which uses fluorometric acid half thioesters (F-MAHT) as a substitute for fluoroacetates, so that the enantioselective Aldol condensation reaction can be carried out, allowing fluoroacetates to be selectively added to organic compounds. Their research findings are published in Nature Chemistry. (Enantioselective aldol reactions with masked fluoroacetates. Nature Chemistry, DOI: 10.1038/nchem.2437)
Acetate is a common structural module in many Natural product and drug molecules, including statins and polyacetyl. For general drugs, one way to obtain their fluoro compounds is to use fluoroacetate as a building block, as its reactivity is very similar to that of acetate. However, the problem arises that the Aldol condensation reaction of fluoroacetates often produces racemic mixtures. For drug molecules, chirality is crucial for their biocompatibility. The left and right handed molecules contained in racemic mixtures are often difficult to separate. Therefore, the ideal scenario is that the reaction of fluoroacetate itself has enantioselectivity.
The strategy designed by Saadi and Wennemers is to use Meldrum acid, that is, cyclic (methylene) isopropyl Malonic acid as the precursor to produce F-MAHT. Meldrum acid is a rigid ring structure, and fluorine can replace the hydrogen atom between the two carbonyl groups on Meldrum acid in three steps. Then, the compound reacts with Silane to Thiophenol, undergoes a nucleophilic ring opening reaction, produces Silane ester intermediate, and is hydrolyzed to F-MAHT.
The advantage of F-MAHT instead of fluoroacetate in Aldol condensation reaction is that it allows mild and selective reaction conditions, as well as continuous generation of carbon dioxide gas, thus driving the chemical reaction toward the product direction. In addition, the use of Quinidine urea catalyst will control which side of F-MAHT reacts with aldehyde. Chemists have further optimized the conditions of this reaction, enabling them to obtain various fluorinated aldehyde alcohol products through the reaction of F-MAHT derivatives with various aromatic and aliphatic aldehydes, while controlling enantioselectivity.
They used this method to carry out a short Total synthesis of Atorvastatin (Lipitor) fluoride analog, which not only obtained the expected product, but also achieved a total yield of 30%. The key step involves the F-MAHT Aldol condensation reaction and the reduction to fluoroaldehyde intermediates. Through this experiment, they demonstrated that F-MAHT can also replace fluoroacetaldehyde. Fluoroacetaldehyde has high reactivity and can produce a complex mixture. Saadi and Wennemers' method overcomes this problem.
Just like some other compounds, such as the fluoride version of hydrocortisone, which exhibits enhanced biological activity (more than 10 times), chemists hope that this mechanism will open up new avenues for the development of numerous other fluorinated drugs, with the aim of improving drug performance.