26 November 2012
Technion researchers found a novel solution to a major problem in organic synthesis that has to date never been resolved, despite worldwide intensive efforts. The Technion team successfully prepared a new molecular framework possessing a challenging asymmetric center in a single chemical step from easily available starting materials. Until now, by lack of available efficient strategies, very few attempts were made and they were all based on long and tedious approaches. This is a significant scientific breakthrough in synthesis, which could lead to a considerable reduction in the production of pharmaceuticals. This groundbreaking discovery is reported by the popular scientific journal “Nature.”
“Synthetic organic synthesis is a science that deals with the building of complex organic molecules from simpler elements,” explains Professor Ilan Marek from the Schulich Faculty of Chemistry at Technion, whose team of researchers were responsible for this major breakthrough. “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” continues Professor Marek.
Although, there are still molecular frameworks that are extremely challenging to prepare, the real question of the 21st century is no longer “can we synthesize this molecule”, but rather “how can we synthesize it efficiently, using the fewest number of steps, with optimum convergence, with as little as possible functional group transformations, little or no by-products and maximum atom-efficiency and at minimal cost.” Over the years, Professor Marek’s research team developed several innovative new synthetic methods that not only fulfilled these requirements, but also gave solutions to challenging problems in organic synthesis.
One of these critical challenges is the formation of chiral all-carbon quaternary stereogenic centers in acyclic systems. A chiral molecule is a type of molecule that has a non-superposable mirror image. Human hands are perhaps the most universally recognized example of chirality: the left hand is a non-superposable mirror image of the right hand; no matter how the two hands are oriented, it is impossible for all the major features of both hands to coincide. This difference in symmetry becomes obvious if someone attempts to shake the right hand of a person using his left hand, or if a left-handed glove is placed on a right hand. This characteristic is also present in organic molecules and two mirror images of a chiral molecule are called enantiomers.
Many biologically active molecules are chiral, including the naturally occurring amino acids (the building blocks of proteins) and sugars. In biological systems, most of these compounds are of the same chirality and understanding the origin of chirality may shed some light on the origin of life. In many cases, both enantiomers of a specific material can affect the human body in completely different ways, and therefore understanding these chiral molecular characteristics is of great importance for the pharmaceutical and food industries. The most infamous case of medical disaster was caused by a misunderstanding of the different pharmacological characteristics of two enantiomers of the same material, known as Thalidomide which caused severe birth defects. Many infants were born without limbs because the drug Thalidomide, which was administered to their mothers, could in-vivo interconvert the two enantiomers.
In the context of building molecules, the aldol reaction is one of the most versatile carbon-carbon bond formation processes available to synthetic chemists but also a critical biological reaction in the context of metabolism. However, coming back to efficiency, the aldol reaction combines only two components with the creation of only one new carbon-carbon bond per chemical step. As discussed previously, better efficiency is now necessary in organic synthesis in which several new carbon-carbon bonds should be formed. Moreover, the construction of chiral all-quaternary carbon centers could not be achieved in the previously aldol-based methodologies. In the most recent report published in Nature by Professor Marek and his colleagues, a very efficient solution to this problem has been reported through a completely different approach. In a single-pot operation, starting from classical hydrocarbons, the formation of aldol products containing the desired all-carbon quaternary stereocenter have been prepared through the concomitant formation of three new bonds. This groundbreaking discovery represents an innovative solution to a challenging synthetic problem.
For the development of original synthetic approaches, Professor Ilan Marek received the prestigious Royal Society Chemistry Organometallic Award (2011) and in 2012 the Janssen Pharmaceutica Prize for Creativity in Organic Synthesis.