by Hai Dao
In June 2009, when the World Health Organization declared the A/H1N1 influenza a “pandemic”, governments around the world stockpiled Tamiflu. Oseltamivir, the active substance of Tamiflu, suddenly switched from being an esoteric term to being a central topic of social media around the world. Five years later, in October 2014, as the number of Ebola cases keeps increasing in African countries, along with reports of infections in Europe and the U.S., the fears of a global epidemic has spread among nations. Although they are still in an experimental stage, the drugs brincidofovir, ZMapp and TKM-Ebola might become our essential weapons in the battle against a potentially global epidemic before the mass production of Ebola vaccine. In molecular biology and pharmacology, oseltamivir and brincidofovir are classified as small molecules approximately the size of a glucose molecule, while ZMapp and TKM-Ebola are large molecules approximately the same size as an antibody (Figure 1). The ability of chemists to create molecules, either small or large, has resulted in the medical revolution in the 20th century, and continues to play a central role in the discovery of new drugs. However, many people still view chemistry as something to be scared of, and even avoided. One reason could be the use of scientific notation (chemical formulas, structural formulas and arrows) that is not accessible to the general public. Here I use the concepts of Lego and ball-and-stick models in an attempt to convey the beauty of these small molecules and to explain how chemists create these molecules in the laboratory.
Consider the scenario of a child playing with Lego: the child builds complex structures from simple Lego bricks. In the process of making a Lego model, the child first selects the bricks and then connects them together, piece by piece, until he/she finishes the target structure. Chemists, in a very similar way, build complex molecules from simple building blocks. However, since the size of the blocks that chemists use (molecules, atoms) is about ten million times smaller than the size of a Lego brick, the ways these tiny pieces fit together in the form of chemical bonds are different from connecting two Lego bricks. When the child places two Lego bricks on top of one another, friction holds them together. In contrast, a chemical bond can be viewed as the attraction between atoms at the nano-scale (Figure 2). When investigating a chemical reaction, one of the first things chemists do is to determine an electrophile (an electron-loving molecule or fragment), and a nucleophile (a nucleus-loving molecule or fragment). When two molecules approach each other, interactions between the negatively charged atoms of the nucleophile and the positively charged atom of the electrophile occur, and in certain cases, these interactions result in the formation of chemical bonds.
When playing with Lego, the child learns to select the bricks by comparing the target structure with the available starting blocks. On the other hand, at the planning stage, chemists do the reverse. They use a method called retrosynthetic analysis to design the route to build complex molecules, normally without assumptions regarding starting materials. Retrosynthetic analysis is similar to the concept of reverse engineering: chemists start with the complex, target molecules and then hypothetically break chemical bonds in various ways to arrive at simpler molecules, with the process being repeated until commercial or known starting materials are reached. In the context of a Lego game, this is similar to a case of a child breaking apart a Lego structure to create a smaller structure and repeating the process until they are left with the basic bricks. Since there are many bonds in a molecule, the decision on what bonds must be broken and the order of bond breaking is important. These decisions are often based on the knowledge of bond formations (chemical reactions) as well as the structure of molecules. This process involves imagination and creativity. A good retrosynthetic analysis not only results in a concise plan for making molecules but also inspires the invention of new chemical reactions and reagents, which in turn can be useful tools for creating other complex molecules.
After designing the backward blueprints, chemists will put it into practice in the forward direction to build the target molecules. Just as the child’s task is to find the right Lego bricks in order to connect them together, a chemist’s task is to find the right starting materials (nucleophiles, electrophiles) and other parameters including temperatures, pressure, and reaction time to create the desired chemical bond. The process includes conducting reactions, isolating products and analyzing data, and involves a lot of trial and error. In addition, chemists often have to revise the initial blueprint in order to progress towards the target molecules. Thus, the synthesis of a complex molecule may take years of effort. A successful synthesis of a complex molecule in the laboratory is often regarded as a scientific achievement as well as a creation of art.
Figure 4 presents a project in our laboratory in ball-and-stick models. The target molecule is prednisone, an immunosuppressant drug. In the beginning, we strategically planned to break the two bonds (shown with arrows) to transform prednisone into simpler fragments A and B. In the forward direction, the negatively charged fragment A (a nucleophile or a nucleus-loving molecule) is thought to react with positively charged fragment B (an electrophile or a electron-loving electron molecule) to form the first chemical bond. The second bond can theoretically be achieved using a more complicated reaction called an oxidative coupling. After working on this project for three years, we discovered that fragment A’, a derivative of A, can be used to connect with fragment B and fragment C to make compound D, which has a similar structure to prednisone. Our laboratory is continuing to investigate how to transform compound D to prednisone. Importantly, the discovery of fragment A’ has inspired the development of a new method for chemical bond formation, which could potentially be used for the synthesis of other classes of compounds.
The process of building complex molecules involves creativity, problem-solving skills as well as a significant amount of work. It requires years of learning and experience. However, the world of molecules and atoms can be intuitively understood with the simple ideas of positive and negative interactions. With this notion, the art of creating molecules, in part, can be appreciated from learning the process of building Lego structures. Importantly, these creative achievements have been, and will continue to be, our essential weapons against diseases.
Hai Dao is a 2011 fellow of the Fulbright Science & Technology Award, from Vietnam, and a PhD student in Organic Chemistry at The Scripps Research Institute.