Researchers discover method to synthesize useful and unique compounds

Japanese researchers have discovered a method to synthesize useful and unique compounds called axially chiral NC compounds.

“Axially chiral NC compounds” are important chiral molecules with various applications in medicinal chemistry and chiral technology. However, there is little research on ways to synthesize them enantioselectively (asymmetrically), to obtain useful forms of the compounds.

Researchers at the Shibaura Institute of Technology, Japan, rectified this problem by developing a catalytic enantioselective method to synthesize various axially chiral NC compounds. A recent article in Accounts of Chemical Research summarizes their accomplishments.

Atropisomers are a class of stereoisomers (chemical compounds that differ in the spatial arrangement of atoms) resulting from restricted rotation around a single bond and have various applications in chemistry.

To date, most research on atropisomers has focused on “biaryl atropisomers” (due to the restriction of rotation around a carbon-carbon bond), but it is also possible that atropisomers are the result of restrictions of rotation around a nitrogen-carbon bond (NC).

These axially chiral NC compounds are found in various natural products and bioactive compounds and therefore have promising applications in medicine and agriculture. In addition, these are known to be useful as chiral building blocks and chiral ligands.

Of course, before researchers can take advantage of such applications, they must develop a workable method to synthesize them.

Although a number of bioactive compounds and natural products possessing an axially chiral NC structure have recently been discovered, no efficient synthetic method was known. “

Osamu Kitagawa, Professor, Shibaura Institute of Technology (SIT)

To solve this problem, Professor Kitagawa and his team have spent the last decades developing efficient methods for the synthesis of axially chiral NC compounds. In an article recently published in Chemical research accounts, Professor Kitagawa summarizes the achievements of his team since 2002.

In 2001, Prof. Kitagawa’s group began studying a never-before-attempted asymmetric catalytic synthesis of ortho-tert-butyl anilides and other axially chiral NC compounds.

In 2005, they discovered that the reaction of achiral secondary ortho-tert-butylanilides with 4-iodonitrobenzene in the presence of a chiral palladium (Pd) catalyst (enantioselective catalytic aromatic amination) resulted in the highly enantioselective (asymmetric) synthesis of NC N- axially chiral. arylated ortho-tert-butylanilides.

They then experimented with adapting this intermolecular N-arylation reaction for use in intramolecular reactions, and their efforts led to the synthesis of compounds called “axially chiral NC lactams” (which had high optical purities). Importantly, these reactions represented the first enantioselective syntheses of axially chiral NC compounds with a chiral catalyst.

Researchers continued their work using chiral Pd-catalyzed intramolecular N-arylations to perform enantioselective syntheses of axially chiral NC derivatives of quinoline-4-one and phenanthridin-6-one.

They also used various Pd catalyzed chiral reactions to prepare optically active NC axial chiral compounds called N- (2-tert-butylphenyl) indoles, 3- (2-bromophenyl) quinazolin-4-ones and N- (2-tert – butylphenyl) sulfonamides.

Professor Kitagawa’s research has led to the successful synthesis of potentially useful compounds, such as an axially chiral NC mebroqualone which acts as an agonist of specific receptors found in the brain called “GABA receptors” (and which has potential therapeutic properties).

In fact, since 2005, the enantioselective synthesis of axially chiral NC compounds has become a subject of considerable interest to chemists outside of Professor Kitagawa’s research team.

For example, the literature on the synthesis of axially chiral anilides with catalytic enantioselective aromatic aminations dates back to 2005, with a research article by Professor Kitagawa’s team, but since then other research groups have published more than 70 Original papers concerning the highly enantioselective synthesis of various axially chiral NC compounds using chiral catalysts.

In addition, the team’s 2010 article on the enantioselective catalytic synthesis of axially chiral NC indoles represented an important contribution to the development of axially chiral indole chemistry, and various research groups have since developed asymmetric catalytic syntheses for various indole derivatives which include a chiral C? C axis or a chiral axis NC. Professor Kitagawa himself considers the work of his laboratory to have important applications to “the synthesis of optically active drug compounds and natural products with axial chirality NC”.

In conclusion, Professor Kitagawa’s research team has succeeded in developing catalytic enantioselective syntheses of axially chiral NC compounds.

This work has inspired other research teams to make further contributions in the same field and has led to exploitable synthetic pathways for bioactive compounds with potential medicinal value. Professor Kitagawa predicts that the asymmetric catalytic synthesis of axially chiral NC compounds will continue to gain attention, thanks to the potential uses of these compounds in a wide range of fields.