The Importance of Synthetic Organic Chemistry in Drug Discovery

In recent years, many pharmaceutical companies have chosen to reduce their R&D investment in chemistry, viewing synthetic chemistry more as a mature technology and less as a driver of innovation in drug discovery. Moreover, there seems to be an underlying current of thought that hard work and determination could offset the elegance of design and creative ideation. We coldheartedly believe that excellence and innovation in synthetic chemistry will continue to be critical to success in all phases of drug discovery and will not be commoditized at least in the foreseeable future.

Over the past century, innovations in synthetic methods have changed the way scientists think about designing and building molecules, enabling access to more expansive chemical space and to molecules possessing the essential biological activity needed in future investigational drugs discovery. Innovation in synthetic chemistry provides opportunity to gain more rapid access to biologically active, complex molecular structures in a cost-effective manner that can change the practice of medicine.

An outstanding example of the transformative power of synthetic chemistry in drug discovery is the application of carbenoid N-H insertion chemistry to the synthesis of b-lactam antibiotics. The application of ring closing metathesis chemistry has been transformative in the synthesis of many HCV NS3/4a protease inhibitors of varying ring sizes and complexity, including six approved drugs: simeprevir, paritaprevir, vaniprevir, grazoprevir, voxilaprevir, and glecaprevir. Ring closing metathesis chemistry enabled the discovery of these and related macrocycles, allowing rapid assembly of complex bioactive molecules and broad exploration of SAR to address a range of properties.

Owing to the diverse biological activity of nitrogen-containing compounds, the discovery of Pd-catalyzed and Cu-catalyzed cross-coupling reactions of amines and aryl halides to form C-N bonds resulted in the rapid implementation of these synthetic methods in the pharmaceutical industry.

The ability of the pharmaceutical industry to discover molecules to treat unmet medical needs and deliver them to patients efficiently in the face of an increasingly challenging regulatory landscape is dependent on continued invention of transformative, synthetic methodologies. To this end, investment in research directed toward synthetic methods innovation and developing new technologies to accelerate methods discovery is essential.

Over the past 20 years, several scientists have been recognized with the Nobel Prize for the invention of synthetic methodologies that have changed the way chemists design and build molecules. Each of these privileged methods — asymmetric hydrogenation, asymmetric epoxidation, olefin metathesis, and Pd-catalyzed cross-couplings — have broadly influenced the entire field of synthetic chemistry, but they have also enabled new directions in medicinal chemistry research. Of particular interest are new synthetic methods that enable medicinal chemists to control reactivity in complex, drug-like molecules, access nonobvious vectors for SAR development, and rapidly access new chemical space or unique bond formations.

As the development of transition metal–catalyzed processes has advanced, application of cutting edge methods to the predictable activation of C-H bonds for functionalization of complex lead structures can enable novel vector elaborations, changing the way analogs are prepared. In particular, late-stage selective fluorination and trifluoromethylation of C-H bonds in an efficient, high-yielding, and predictable fashion permits the modification of lead compounds to give analogs that potentially possess greater target affinity and metabolic stability without resorting to de novo synthesis.

Adoption of photoredox catalysis in the pharmaceutical industry has been rapid, owing to the practicality of the process, the tolerance to functional groups in drug-like candidates, and the activation of nonconventional bonds in drug like molecules. Application of photoredox catalysis to the Minisci reaction was reported, enabling the facile and selective introduction of small alkyl groups into a variety of biologically active heterocycles such as camptothecin.

Even more remarkable transformations are being reported via synergistic catalysis, where both the photocatalyst and a co-catalyst are responsible for distinct steps in a mechanistic pathway that is only accessible with both catalysts present. For example, the combination of single-electron transfer–based decarboxylation with nickel-activated electrophiles has provided a general method for the cross-coupling of sp²-sp³ and sp³-sp³ bonds. This method establishes a new way of thinking about the carboxylic acid functional group as a masked cross-coupling precursor, expanding the synthetic opportunities for a functional group that is ubiquitous in chemical feedstocks. Furthermore, leveraging synergistic catalysis with photoredox has resulted in the discovery of milder conditions for C-O and C-N cross couplings, allowing application of these methods to more pharmaceutically relevant substrates.

Despite the many advances described above, the pace and breadth of molecule design is still constrained because of unsolved problems in synthetic chemistry. Many opportunities still remain to advance the field, such that synthetic chemistry will never constrain compound design or program pace and should actually inspire access to uncharted chemical space in the pharmaceutical industry.

Key unsolved problems in synthetic chemistry included selective saturation and functionalization of heteroaromatics, concise synthesis of highly functionalized, constrained bicyclic amines, and C-H functionalization for the synthesis of a,a,a-trisubstituted amines. Other areas, such as selective functionalization of biomolecules and synthesis of noncanonical nucleosides, are emerging areas of high potential impact.

Synthetic chemistry has historically been a powerful force in the discovery of new medicines and is now poised to have an even greater impact to accelerate the pace of drug discovery and expand the reach of synthetic chemistry beyond the traditional boundaries of small-molecule synthesis. New methods of synthesis can greatly expand the rate of molecule generation while also providing opportunities to routinely synthesize complex molecules in the course of drug discovery.

Continued investment in synthetic chemistry and chemical technologies has the promise to advance the field closer to a state where exploration of chemical space is unconstrained by synthetic complexity and is only limited by the imagination of the chemist. Advancements in synthetic chemistry are certain to remain highly relevant to the mission of inventing new medicines to improve the lives of patients worldwide.