2018-06-01
Although we have recently seen some negative news about fluoride, such as the environmental pollution, and the potential danger of fluorinated polymers to the human body. However, in fact, there is no need to talk about "fluorine". Fluorine is the most electronegative atom in the Periodic Table, and has a wide range of applications in organic and medicinal chemistry. In fact, replacing hydrogen with fluorine can increase the biological activity of the drug often, and because the carbon-fluorine bond is strong, it is more resistant to the metabolic chemical environment within the receptor. For this reason, many chemists are keen to make fluorinated derivatives of pharmaceuticals. However, for some organic compounds, it is difficult to obtain functionalized fluorinated compounds.
Recently, chemists Jakub Saadi and Helma Wennemers of the Swiss Federal Institute of Organic Chemistry in Zurich developed a generic bionic method using fluoromalonic acid half thioesters (F-MAHT). As an alternative to fluoroacetate esters, the enantioselective aldol condensation reaction is carried out so that fluoroacetate esters can be selectively added to organic compounds. Their research was published in Nature Chemistry. (Enantioselective al- idide with masked fluoroacetates. Nature Chemistry, DOI: 10.1038/nchem.2437)
Acetate is a common structural moiety in many natural products and drug molecules, including statins and polyacetylation. One way to obtain a fluorinated compound is to use fluoroacetate as a building block for common drugs, because its reactivity is very similar to acetate. However, the problem arises that the aldol condensation of fluoroacetates tends to generate racemic mixture products. Chirality is crucial for its biocompatibility for drug molecules. The left- and right-handed molecules contained in the racemic mixture are usually difficult to separate. Therefore, it is desirable that the reaction of this fluoroacetate itself has enantioselectivity.
The strategy designed by Saadi and Wennemers is to use Meldrum acid, i.e., isopropyl malonate as a precursor, to produce F-MAHT. Meldrum acid is a rigid ring structure. Fluorine can replace hydrogen atoms between two carbonyl groups on Meldrum acid in three steps. This compound is then reacted with silylated thiophenol, undergoing a nucleophilic ring-opening reaction to produce a silyl ester intermediate which is then hydrolyzed to F-MAHT.
The advantage of using F-MAHT instead of fluoroacetate for the aldol condensation reaction is that it allows mild and selective reaction conditions, as well as continuous production of carbon dioxide gas, which drives the reaction toward the product. In addition, the use of a quinidine urea catalyst will control which side of the F-MAHT reacts with the aldehyde. The chemists optimized the conditions of the reaction, and they were able to obtain a variety of fluoroaldol products under the control of enantioselectivity through the reaction of F-MAHT derivatives with various aromatic and aliphatic aldehydes.
They used this method to perform a short total synthesis of atorvastatin (lipitor) fluorinated analogs, which not only gave the desired product, but also reached a total yield of 30%. One of the key steps involved the F-MAHT aldol condensation reaction and the reduction to the fluoroaldehyde intermediate. Through this experiment, they demonstrated that F-MAHT can also replace fluoroacetaldehyde. Fluoroacetaldehyde is highly reactive and produces a complex mixture. Saadi and Wennemers' method overcomes this problem.