Professor Scott Snyder, formerly of Columbia University and The Scripps Research Institute, joined the Department of Chemistry at the University of Chicago in Autumn 2015. An avid educator, Snyder has co-authored several books, including the textbook used in Chicago’s undergraduate organic chemistry sequence, a handbook on natural product synthesis, and a primer for new faculty called Teach Better, Save Time, and Have More Fun. His gift for taut description also extends to his research aims: “We want to learn how to synthesize complex structures, come up with new tools to do so, and figure out what the biomedical or biochemical potential of those structures are.” Yet while many chemists may share these goals, Snyder’s focus on developing reagents and broadly applicable strategies for the synthesis of complex natural products makes his approach particularly effectual.
“We make complex natural products,” he explains, noting that over half of the most widely sold pharmaceuticals either comes directly from nature, or is derived from nature. Some natural-product based drugs include aspirin, a derivative of willow tree leaves, the breast cancer drug taxol, which comes from the Pacific yew tree, and the antibiotic vancomycin, which comes from soil bacterium Amycolatopsis orientalis. “As creative as we are as chemists, we never would have come up with a structure like [vancomycin],” says Snyder. “What natural products can teach us, apart from whether or not they become medicinal agents, is how to target biomolecules.” Vancomycin, for instance, targets specific peptide chains on bacteria through a series of five hydrogen bonds, thereby interrupting cell wall synthesis in Gram-positive bacteria. “Often, when I look at molecules we’re thinking of synthesizing, I have questions like, ‘Why are the atoms in this particular order?’ ‘Is there a reason why this pattern exists?’ ‘Does this allow for a selective interaction with a biomolecule?’”
While Snyder has focused on molecules with biomedical utility, his efforts are not disease-driven. “For me, it’s molecule first and foremost,” he says. “I want to make sure that whatever we are engaged in, we will have opportunities to develop new reagents and new tools to put molecules together more efficiently.” Recalling his early interest in halogenated marine natural products, Snyder explains that his approach was motivated by efforts to develop tools that could be modified for more general use. “[Could] we come up with appropriate chemical reagents to very simply put in the same atoms as what nature often does with exquisitely tailored enzymes? Although we have a lot of reagents to do chlorinations or brominations of simple alkenes, we could not do similar processes for a number of more complex, naturally-relevant substrates in a laboratory setting. We used that as inspiration to come up with tools to solve this problem. One, known as BDSB (for Et2SBr•SbBrCl5) has been commercialized and sold by Sigma-Aldrich in a number of countries throughout the world.”
Through such an approach, Snyder has gained useful insights on the limitations of the field. “[While] we may have come up with twenty ways to do a particular reaction, when you’re working with a more complex molecule, maybe all twenty of those methods fail. That indicates that we may need another tool or approach to solve this particular problem. One of the advantages of working with a more complex molecule is that it may afford a clear sense of where there are limitations in existing tools. The mere fact that there are twenty tools also might indicate that there’s no such thing as a general reaction. We think we may know the rules of reactivity, but a lot of times we actually do not. I have never had a synthetic design ultimately translated in the laboratory from start to finish based on what was originally conceived.”
Whether a consequence or an effective means of addressing this unpredictability, Snyder prefers studying collections of structures. “Typically a plant . . . doesn’t make just a [single] molecule. It will make several related structures, because [it] is still refining what is helping it have organismal survival,” he notes. “For anything that we do, I’m looking for solutions I can then apply to other targets as well. We recently published a paper where we developed a cascade reaction—i.e., a process where, after one reaction happens, it sets the stage for the next and the next—to rapidly assemble a number of critical bonds. Based on that success, we have begun to think about other molecules that have proven difficult to make where this approach may be a successful way of handling certain elements of those molecules as well.”
Recently, Snyder and his lab have focused their attention on alkaloid natural products, including some used in traditional Chinese medicine. “In some cases, we know that these molecules have come from a medicine, but little is known about what it actually does, whether it is the active component, one of several active components, or inactive,” he says. “I believe all natural products exist for a reason. Nature invests a fair amount of ATP energy to produce these structures for that organism’s own purpose. Often they can interact favorably with human biology, and for us it is a question of figuring out what a molecule might be able to do.”
Another long-term interest has been compounds found in red wine, including resveratrol, a molecule that has received popular attention for its potential role in the so-called “French paradox”—the otherwise inexplicable longevity of the French despite a diet traditionally high in fat and cholesterol. “Nature uses resveratrol as a seed to make several hundred structures as a front-line defense against a fungal infection,” he explains. “Once a fungal infection comes along, between two and ten resveratrol [building blocks] will come together to make a whole collection of new structures as a front line defense [that] can allow for organismal survival or at least slow things down so that other resources can be brought to bear to allow for certain plants to survive.”
Though particular molecules have drawn his attention, Snyder’s work broadly aims at the methodological craft of synthetic chemistry. “We do not want several uncontrolled pathways that lead to several dozen structures at once; we want to understand how to make one, and then from there make the next, and then from there make the next. If you had a molecule that had six different places that are chemically similar, could we pick them out one at a time in any order that we might want?” He calls the ideal accomplishment “Star Trek synthesis—you go to this machine, you say, ‘ice cream sundae,’ and boom—it shows up. For organic chemistry of the twenty-first century, I would argue that is one of the field’s main goals—to find the way to tailor a molecule and put in anything we might want in any order we might desire.”
(Irene Hsiao)