Total Synthesis and the Creative Process:
An Interview with K.C. Nicolaou

Kyriacos C. Nicolaou, founding chairman of The Scripps Research Institute (TSRI) Department of Chemistry and L.S. Skaggs Professor of Chemical Biology at The Skaggs Institute for Chemical Biology at TSRI, recently spoke with Jason Bardi of News&Views. Nicoloau described his research, his approach to training graduate students, and the field that builds complex molecules from simpler ones-total synthesis.

Bardi: You have said that total synthesis demands those same traits from a chemist as the creative process demands from an artist. Can you explain this?

Nicolaou: It’s rather complicated to even define art, science, and technology. There is a triangle of art, which is the pursuit of something new, usually associated with esthetics; science, the pursuit of something new, perhaps the understanding of nature; and technology, the application of science.

Those of us who practice total synthesis like to think of ourselves both as scientists and as artists. The molecules that we’re dealing with in chemistry have dimensions, geometries, and symmetries that are esthetically pleasing and, perhaps, artistic. In our business, we design molecules all the time, exercising artistic taste. We also exercise artistic taste in the way that we combine chemical reactions to arrive at a strategy that will lead to the target molecule.

A [composer] combines notes to make a symphony. In a similar way, a synthetic chemist combines chemical maneuvers to make a molecule. That sequence can be appreciated from an artistic point of view. You have to understand the chemistry, of course, to appreciate that.

Also, I can compare the art of the synthesis of a target molecule to the game of chess. If you watch master chess players and you follow their moves in getting to the king, you can appreciate their mastery of the art, their ingenuity, their cleverness. In the same way, if we are making a molecule, we have to go step-wise from the material we can buy, from petroleum, or from crops, or from something we can extract—and we have to make maybe 50 moves before arriving at a very complicated product, such as taxol or vancomycin.

Along the way, we face an opponent. It is an invisible opponent. Nature. We are designing a particular step-—maybe the 35th step—and we don’t know if that step will be allowed by the natural laws. We have to experiment to see if it’s going to work. We anticipate all our moves, and we write them down on a piece of paper. But it never works that way. Nature always counters us.

In the laboratory, we always come up against obstacles to overcome, often not anticipated. These obstacles are actually blessings in disguise, because [they force us to] rise to a higher level of ingenuity and create new chemistry to solve that particular problem.

So you come up with new chemistry?

Absolutely. We invent new chemistry. Most important are the things you discover along the way that remain for everyone to use in the laboratory.

If you practice total synthesis, you are bound to sharpen the tool of organic synthesis. And that’s very necessary today with the human genome deciphered because we need to have the capability of making more molecules faster than before. We need to have more complicated molecules. We need to make them more efficiently. We need to make them in a benign chemical way so that we don’t pollute the environment. And total synthesis continues to be the engine that drives organic synthesis forward, and therefore I think it is still a flourishing, exciting field of investigation.

How is the human genome initiative going to affect total synthesis, and—likewise—how will total synthesis be used as a tool in genomics?

The importance of [total synthesis] is finding ways to increase the pace of producing compounds for biological screening. And this is what the human genome demands—matching all those discoveries in biology with advances in synthetic chemistry that will produce the ligands that we need to modulate the function of the genes.

Eighty percent of the medicines we have in the pharmacy today are small organic molecules, which go into the body, bind certain proteins, and modulate their effect. Now that we have so many more biological targets, we need even more small molecules. We need libraries of small molecules from which we can select the ones that bind to the proteins, the ones that have the right pharmacological profile so that they can become medicines. The bottom line is synthesizing a lot of compounds and testing them against a biological target.

We have to synthesize many compounds to find a few that bind. And even if we find a few that bind, that doesn’t mean they are drugs. We have to fine-tune their structure to make them have the right properties—bioavailability, stability, toxicity, all those things.

Organic synthesis is behind medicinal chemistry, and total synthesis is a branch of organic synthesis. I call it the engine that drives organic synthesis forward, because total synthesis deals with the ultimate challenges of organic synthesis—the most complicated molecules that nature has ever made are in front of the synthetic chemist.

[Total synthesis] also provides a test for the state of the art of chemical synthesis. If you can make taxol, then it means that your state of the art is very powerful. Ten years from now, we need to make much more complicated molecules than taxol. And at that time, I’m sure we’ll be able to do it, because we’ll have more refined tools.


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"A composer combines notes to make a symphony," says Professor K.C. Nicolaou. "In a similar way, a synthetic chemist combines chemical maneuvers to make a molecule."















Persist and withdraw when you are faced with difficulties, redesign the strategies, and try again.”

—K.C. Nicolaou