Osaka, Japan – Diastereomers are structurally identical molecules that are not mirror images of each other. Diastereomers can have different biological activities, potencies or toxicities, which means they can influence biological systems, be separated from one another and more. To fully unlock their potential in organic chemistry, it is important to create the necessary diastereomer, but their creation is a key problem in organic synthesis.
However, a team of researchers at The University of Osaka has found a novel method for creating a diastereomer not typically produced in high quantities from traditional chemical reactions. This exciting discovery will be reported in Nature Communications.
Pharmaceuticals and natural products are complex molecules that are constructed using smaller, simpler molecules as "building blocks". In one such building block, the carbonyl group, a carbon atom and an oxygen atom share a pair of electrons to form a "double bond". Meanwhile, in another block, the α-oxy carbonyl group, a carbon atom is attached to the carbonyl group – known as the α-carbon – and the presence of the existing oxygen atom places this in an oxygen-based group.
In the carbonyl group, the oxygen atom attracts electrons away from the carbon atom, creating a partial positive charge at the carbon atom and making the carbonyl bond electron-poor, or electrophilic. As a result, electron-rich species – known as nucleophiles – can easily break the carbonyl bond by donating a pair of electrons, forming a new bond.
An allyl group, which combines a vinyl group and a methylene bridge, is a nucleophile that can add to an α-oxy carbonyl compound in two ways. This can be either opposite to the α-oxygen ('syn'-adduct is generated.) or on the same side as the α-oxygen ('anti'-adduct is generated.). The high chelation tendency of the α-oxy group preferentially causes the generation of the syn-adduct, meaning that the anti-diastereomer is not obtained in high yield.
However, The University of Osaka team has been able to engineer anti-addition of an allyl to an α-oxy carbonyl compound.
"We selected an allyl with a cage-like structure, an allylatrane. In this molecule, a large number of atoms are bonded to a central atom from Group 14 (such as carbon or silicon)," explains lead author Yuya Tsutsui. "This high coordination number makes the allylatrane highly nucleophilic."
The rigid structure and low Lewis acidity of the allylatrane makes syn-adduct to an α-oxy carbonyl compound difficult. As a result, the anti-diastereomer is obtained as the major product.
"Our strategy is applicable to a wide variety of substrates," reports Makoto Yasuda, senior author. "The anti-diastereomer can be obtained in considerably higher yields than those afforded by traditional methods."
The method developed by the team has the potential to assist manufacturers in producing large quantities of products previously only obtained as minor byproducts. This approach is expected to become a key technology for the synthesis of unique molecules used to make medicines and other bioactive substances.
