Breakthrough in organic chemistry: Asymmetric syntheses of useful, unique chiral compounds
Atropisomers are a class of stereoisomers (chemical compounds that differ in the spatial arrangement of atoms) derived from a restricted rotation around a single bond and have various applications in chemistry. So far, 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 originate from restrictions of rotation around a nitrogen-carbon (N-C) bond. These axially chiral N-C compounds are found in various natural products and bioactive compounds and therefore have promising applications in medicine and agriculture. In addition, they are known to be useful as chiral building blocks and chiral ligands.
Of course, before researchers can take advantage of these applications, they must develop a feasible method to synthesize them. "Although a number of bioactive compounds and natural products with an axially chiral N-C structure have recently been discovered, no effective method of synthesis was known," notes Professor Osamu Kitagawa of the Shibaura Institute of Technology (SIT) in Japan. To solve this problem, Professor Kitagawa and his team have spent the last decades developing efficient methods for the synthesis of N-C compounds with an axially chiral structure. In a paper recently published in Accounts of Chemical Research, Professor Kitagawa summarizes the achievements of his team since 2002.
In 2001, Professor Kitagawa's group began studying a previously untried asymmetric catalytic synthesis of ortho-tert-butyl anilides and other axially chiral N-C 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 aromatic amination catalyst) resulted in the highly enantioselective (asymmetric) synthesis of axially chiral N-aryl ortho-tert-butylanilides. They then experimented with adapting this intermolecular N-arylation reaction for use in intramolecular reactions, and their efforts resulted in the synthesis of compounds called "axially chiral N-C lactams" (which had high optical purities). It is important to note that these reactions represented the first enantioselective enantioselective syntheses of axially chiral N-C compounds with a chiral catalyst.
The researchers continued their work using Pd-catalyzed chiral intramolecular N-arylations to perform enantioselective syntheses of axially chiral N-C derivatives of quinolin-4-one and phenanthridin-6-one. They also used various Pd-catalyzed chiral reactions to prepare optically active axially chiral N-C 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 N-C mebroqualone that acts as an agonist for specific receptors in the brain, called "GABA receptors". (and has potential therapeutic properties).
In fact, since 2005, the enantioselective synthesis of axially chiral N-C compounds has become a subject of considerable interest for chemists outside of Professor Kitagawa's research team. For example, the literature on the synthesis of axially chiral anilides with enantioselective catalytic aromatic aminations dates back to 2005, with one research paper from Professor Kitagawa's team, but since then, other research groups have published more than 70 original papers on the highly enantioselective synthesis of various axially chiral N-C compounds using chiral catalysts. In addition, the team's 2010 paper on the enantioselective catalytic synthesis of axially chiral N-C indoles was 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 that include a chiral C-C axis or a chiral N-C axis. Professor Kitagawa himself considers that the work of his laboratory has important applications for "the synthesis of optically active drug compounds and natural products with N-C axial chirality".
In conclusion, Professor Kitagawa's research team has succeeded in developing enantioselective catalytic syntheses of axially chiral N-C compounds. This work has inspired other research teams to make further contributions in the same field and has led to exploitable synthesis pathways for bioactive compounds with potential medicinal value. Professor Kitagawa predicts that asymmetric catalytic synthesis of axially chiral N-C compounds will continue to attract attention, with potential uses for these compounds in a wide range of fields.
