Breakthrough in Organic Synthesis Expected to Accelerate Development of New Drugs

The particular challenge was the preparation of all-carbon quaternary stereocenters in aldol adducts. This synthesis is critical, as the aldol reaction represents one of the most valuable chemical transformations in organic synthesis.

A stereocenter or stereogenic center is an atom bearing groups such that an interchanging of any two groups leads to a stereoisomer. A chirality center is a stereocenter consisting of an atom holding a set of ligands (atoms or groups of atoms) in a spatial arrangement, which is not superposable on its mirror image. A chiral center is a generalized extension of an asymmetric carbon atom, which is a carbon atom bonded to four different entities, such that an interchanging of any two groups gives rise to an enantiomer.

Enantiomers of each other often show different chemical reactions with other substances that are also enantiomers. Since many molecules in the bodies of living beings are enantiomers themselves, there is often a marked difference in the effects of two enantiomers on living beings. In drugs, for example, often only one of a drug's enantiomers is responsible for the desired physiologic effects, while the other enantiomer is less active, inactive, or sometimes even responsible for unwanted side effects.

In a paper published in the October 24, 2012, online edition of the journal Nature the investigators described a different synthetic approach that involved the formation of two new stereogenic centers - including an all-carbon quaternary one - via a combined carbometalation-oxidation reaction of an organocuprate to give a stereodefined trisubstituted enolate (an organic compound containing a hydroxyl group bonded to a carbon atom, which in turn is doubly bonded to another carbon atom).

They used this method to generate a series of aldol and Mannich products from ynamides with excellent diastereomeric and enantiomeric ratios and moderate yields. This was a significant breakthrough in organic synthesis, which could lead to a considerable reduction in the time required to produce some classes of pharmaceuticals.

“Synthetic organic synthesis is a science that deals with the building of complex organic molecules from simpler elements,” said senior author Dr. Ilan Marek professor of chemistry at the Technion - Israel Institute of Technology. “One of the greatest applications of this new approach is a quick and efficient synthesis of complex natural materials that may be used in pharmaceutical industry. It must be the goal of the 21st century to accomplish more with less. In today’s society, no one can afford to follow the inefficient route of long and tedious synthesis. We should think organic synthesis differently and I am sure that new transformations that were not possible to perform by conventional methods will soon appear.”

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Technion - Israel Institute of Technology