Developing “Green” construction complex molecular structures

Developing “Green” construction of complex molecular structures

10:50 AM, 16th July 2016
Developing “Green” construction of complex molecular structures
Laszlo Kurti, associate professor in the department of chemistry at Rice University.

In an interview Laszlo Kurti, associate professor in the department of chemistry at Rice University with Chemical Today magazine, talks about new methods that render popular metal-catalyzed transformations metal-free giving reliable options for organic chemists.

Tell us about your current research?

The Kurti lab has been exploring several fundamentally new strate­gies and methods for the creation of novel C-C and C-heteroatom bonds that expand the toolbox of synthetic organic chemists and enable the environmentally friendly construction of complex molecu­lar structures. A highly attractive, but currently underdeveloped approach is the utilization of weak bonds (e.g. N-N, N-O) as a driving force to achieve the rapid formation of much stronger bonds under mild conditions. During the past three years, the Kurti laboratory has successfully exploited these weak bonds and developed a number of transition-metal-free direct C-C and C-N bond-forming reactions,

Such as:

• chiral acid-catalyzed atropose­lective synthesis of functional­ized biaryls

• direct arylation of arenes

• aerobic direct and regiospecif­ic-arylation of ketones

• low-temperature intramolecular C(sp2)-H amination of arenes, and

• primary amination of arylboronic acids as well as aryl-Grignard reagents.

In addition, Kurti laboratory played a crucial role in the discovery of the dirhodium-carboxylate-catalyzed, direct and stereospecific synthesis of unprotected N-H and N-Me aziri­dines from olefins, a transformation that has eluded synthetic chemists for decades.

How chiral biaryl com­pounds can help in the making of drug com­pounds and what makes them effective in this process?

Chiral non-racemic functionalized biaryl compounds are used as high­ly efficient catalyst (or as ligands for transition metals that together make up a chiral metal catalyst) to set up a particular configuration (R or S) at a chiral carbon atom that has four different substituents. Chi­ral non-racemic functionalized biar­ylsare popular both in the chemical and pharmaceutical industry as catalysts ($1 billion/year in sales) and are used for the synthesis of agrochemicals as well as drug intermediates on multi-ton scales (some of them on multi-hundred ton scale).

This broad utility makes functional­ized biarylsone of the most suc­cessful (if not the most successful) classes of catalysts and are consid­ered to be “privileged”. Privileged catalysts are those that work well regardless of the class of sub­strates being used and the particu­lar mechanism that is operational in the chemical transformation being catalyzed.

Besides being superb catalysts, functionalized biaryls (i.e., two aro­matic rings connected to each other via a C-C bond) are also present in natural products as well as the biaryl substructure is considered to be privileged one in drug discovery. Privileged sub­structures are those that can be decorated in many different ways with substituents and the resulting compounds can become non-pro­miscuous binders for biological macromolecules such as proteins and enzymes. There are many bioactive natural products in which there is one or more functionalized biaryl structural motif. In fact, there are more than 1000 natural prod­ucts that have been isolated and characterized with this substructure and this number is steadily growing – these compounds are potential lead compounds for drug discovery.

What is the main purpose to remove transition metals from the chemical process?

Transition metals and their com­plexes are extremely useful as cat­alysts for a wide range of chemical transformations. However, they are generally costly and toxic. Toxicity is a very important issue especially in the case of compounds that are intended for human use (i.e., phar­maceuticals, food additives, etc.).

The FDA regulates the levels of metal residues in compounds that will be used in clinical trials or have been approved for use as drugs. If a particular active pharmaceutical ingredient (API) is manufactured using transition metal catalysts, chances are that before admin­istering it to human subjects (or patients), a costly removal of the metal residues is necessary via repeated chromatography, recrystallization or a combination of both.

This process can be costly and it leads to inevitable material loss. Therefore, it is desirable to modify synthetic sequences leading to APIs in a way that either:

- transition metals are used early in a synthetic sequence or;

- transition metal-catalyzed reac­tions are replaced by transition metal-free transformations.

If designed properly, the new syn­thetic sequence will avoid transition metals during the last 3-4 steps and thus at the end of the sequence the level of transition metals in the final product will be at the desired level or even below and further costly pu­rification steps on the final API will not be necessary.

Explain in brief about single-flask process, why you opted for this process?

A single-flask (also known as “one­pot”) synthesis is an effective meth­od for both carrying out several transformations and forming sever­al bonds in a single reaction vessel. At the same time, several purifica­tion steps are avoided and chemi­cal waste generation is minimized. For the reasons above, single-flask processes are highly desirable and many chemical transformation lend themselves to this approach if so designed.

Our new biaryl synthesis was amenable for a one-pot approach as the mixed acetal formation was immediately followed by sigma­tropic rearrangement that gener­ated the new carbon-carbon bond. There is a clear advantage here because we do not have to isolate intermediates and subject them to separate reaction conditions to obtain the final functionalized biaryl products. In addition, the reaction conditions are very simple and the starting materials are inexpensive – at the end we obtain a highly valu­able product and due to the opera­tional simplicity an entire library of these compounds can be obtained in short order.

Our new method breaks new ground on multiple fronts as it provides synthetic access to non-C2-symmetrical functionalized biaryls:

• In only a single operation in one reaction vessel (i.e, single-flask or one-pot)

• Starting materials are cheap

• Waste stream is minimal

• No-toxic metals are needed as the process is organo catalytic which means that a small organic molecule acts as a catalyst instead of expensive and scarce transition metals

• A vast new chemical space is accessed with the economical and scalable synthesis of 41 non-C2-symmetrical biaryls

With the disclosure of this method, the organic chemistry community at large in academia as well as in industry can prepare any of these non-C2-symmetrical biaryls and evaluate each of their enantiomers as new catalysts for myriad of known and new transformations.

What is the role of single-enantiomer com­pounds in drug making process?

The early 1960s has seen the tragedy of the anti-nausea drug called thalidomide (brand name in Europe was Contergam) that was supposed to ease the symptoms of nausea in pregnant women. How­ever, one enantiomer of this drug was toxic to the foetus (i.e, terato­genic effect) and thousands of ba­bies were born without limbs. This fiasco prompted the FDA to require the testing of both enantiomers of chiral compounds to see if their biological effects are different and find out if any of the enantiomers is actually toxic. Today very few drugs that are chiral are sold as race mates (i.e., 50:50 mixture of the enantiomers) but rather chiral drugs are sold as single-enantiomers that are stable under physiological con­ditions (i.e., the enantiomers should not interconvert in vivo).

It is estimated that by 2020, 95 percent of all chiral drugs will be sold as single-enantiomers. Due to the steady increase of chiral drugs on the market that are sold as single enantiomers, organic chemists urgently need to address the en­antioselective synthesis of chiral building blocks with ever-increasing complexity and challenges.

The preparation of novel chiral com­pounds will require new catalysts that represent new (i.e., untapped) chemical space - this is where contributions from the Kürti lab is really important given the fact that synthetic access to functionalized biaryls (i.e., privileged catalysts) has been very challenging and costly. Especially non-C2-sym­metrical biaryls have been shown to be effective catalysts in many cases in which the C2-symmetrical versions are ineffective or give poor results. However, synthetic access to non-C2-symmetrical versions of these functionalized biaryls is exceedingly difficult - most of the time people can only isolate these non-C2-symmetrical compounds as side products during the synthesis of C2-symmetrical functionalized biaryls.

What are the most challenging issues for your area of research?

Transition metal-free transforma­tions that are as efficient as the corresponding transition metal-catalyzed reactions are still relatively rare, but this area of critically im­portant research is growing rapidly. Especially the functionalization of aromatic and heteroaromatic rings is where more effort is needed. While transition metal catalysts such as Pd, Rh, Ir can bring about C-H activation, transition metal-free processes will have to rely on clever rearrangements and novel reagents to bring about the desired C-H functionalization under mild conditions and with high efficiency.

The Kurti lab continues to explore new methods that render popular metal-catalyzed transformations metal-free, thus giving several reli­able options in the hands of practic­ing organic/medicinal chemists.

© Chemical Today Magazine

  •  See the Interview Coverage in Chemical Today magazine (Pg 44)

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



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