Finding new way drug development

Finding a new way of drug development

11:19 AM, 18th November 2017
Finding a new way of drug development
Uttam Tambar, associate professor at the W. W. Caruth, Jr. Scholar in Biomedical Research, The University of Texas Southwestern Medical Center at Dallas.

In an interview, Uttam Tambar with Chemical Today Magazine talks about his research on streamlining the synthesis of pharmaceutical drugs by making internal alkenes. 

Tambar is an associate professor at the W. W. Caruth, Jr. Scholar in Biomedical Research, The University of Texas Southwestern Medical Center at Dallas.

Research insight on speedy drug development.

For many years, chemists have sought to develop new reactions to the direct conversion of inexpensive feedstock hydrocarbons into valuable materials such as pharmaceuticals. However, internal alkenes, which are one of the most abundant classes of hydrocarbons, contain many carbon-hydrogen bonds. The selective transformation of one carbon-hydrogen bond into a new bond is a significant challenge, resulting in difficult to separate mixtures of compounds. If the goal is to synthesize a pharmaceutical drug from a hydrocarbon starting material, the indiscriminate transformation of multiple carbon-hydrogen bond would render the chemical process useless, because we would generate potentially dangerous side products in addition to the desired product.

Our group has developed a method for the direct conversion of a variety of double bond-containing internal alkenes into multifunctional intermediates through the implementation of a chiral catalyst and a unique oxidant. These multifunctional compounds, which are obtained in high purity, are readily transformed into an assortment of molecules that will streamline the synthesis of future pharmaceutical drugs.

New chemical reaction that accelerates drug development.

Our group has developed a new reaction that selectively oxidizes internal alkenes. The products of this reaction are useful building blocks that can accelerate the drug development process.

Applications of these molecules.

We are now able to use internal alkenes as substrates for enantioselective allylic oxidation. Alkenes, in general, are ideal starting points for drug production, because they are inexpensive and abundant. Internal alkenes, in particular, are the most common class of alkenes found among organic substrates. But historically they have also been the most challenging class of unsaturated hydrocarbons to be used as substrates for enantioselective allylic oxidation.

Insight into chiral catalyst used in the research.

In our research, we utilize an antimony-BINOL complex as the chiral catalyst. Pioneered by Corey and co-workers, the complexation of SbCl5 and BINOL results in the formation of a Lewis acid assisted Brønsted acid, in which the protons of BINOL are rendered more acidic due to coordination with SbCl5. In our system, we believe the oxidant is activated by the SbCl5-BINOL complex through a LUMO lowering effect.

Bringing a change in the pharmaceutical industry.

We believe our research could streamline the synthesis of pharmaceutical drugs by making internal alkenes, which are the most common class of alkenes found among organic substrates, viable starting points for drug production.

Comparing with other ongoing researches in this area.

Allylic C–H oxidation of alkenes for the production of valuable pharmaceutical agents is most useful when the products are synthesized with significant chemo-, regio- and stereocontrol. Traditional strategies have olefin utilized tethered directing groups to control the position of allylic oxidation. We developed a unique and general approach that relies on the nature of the external oxidant to impart regiocontrol, which has enabled simple and complex alkenes to be used as substrates.

Unlike terminal alkenes, which only contain a single set of enantiotopic allylic protons, internal alkenes possess two sets of protons on either side of the olefin moiety, thereby posing the additional challenge of regioselectivity for unsymmetrical olefins (Fig. 1B). Furthermore, when the resulting product is an internal alkene, the issue of E/Z selectivity subsists. The inability to control indiscriminate C–H functionalization of electronically and sterically similar allylic protons, therefore, has the potential to produce a mixture of regio-, diastereo-, and enantiomeric isomers that are difficult to separate via preparative methods.

Commercializing the research.

We have begun to talk to pharma companies who are interested in implementing our research into their discovery platforms. We have also initiated discussions with two chemical vendors to commercialize our technology.

Plans for future research.

We are interested in exploring useful transformations of the products that we can generate with our allylic oxidation technology. We are also interested in exploring the utility of the allylic oxidation method in more functionalized molecular settings, which will enable the synthesis of complex target molecules. We also hope to while also generalize this mode of catalysis to other unprecedented reactions of alkenes.

Challenges faced in carrying out the research.

It was challenging for us to find a general solution to selectively functionalize internal alkenes. Unlike terminal alkenes, which only contain a single set of enantiotopic allylic protons, internal alkenes possess two sets of protons on either side of the olefin moiety, which presents the additional challenge of regioselectivity for unsymmetrical alkenes. In addition, since the resulting product is also an internal alkene, there is an issue of E/Z olefin selectivity in the product. The inability to control C–H functionalization of electronically and sterically similar allylic protons has the potential to produce a mixture of regio-, diastereo-, and enantiomeric isomers that are difficult to separate via preparative methods.

Other ways to achieve speedy drug development.

Synthetic chemists have always been enamoured by the prospect of selectively altering a single C–H bond in any three-dimensional molecule without affecting other energetically similar C–H bonds. While enzymes have evolved to perform these selective transformations in nature, the site-selective and stereoselective functionalization of C–H bonds with synthetic reagents and catalysts remains a Holy Grail in organic chemistry. A general solution to this problem would provide more efficient and practical strategies for designing and manipulating small molecules, which would enable speedy drug development.

© Chemical Today Magazine


See the Interview in Chemical Today magazine

https://www.worldofchemicals.com/digitalissue/chemical-today-november-2017/25

View the magazine on Mobile, download the Chemical Today magazine app

http://bit.ly/21W5H0z

http://apple.co/1ZwID77

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