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This field is augmented by the discovery of new structures in nature. Nature has not revealed all its secrets to us yet. In the forest, there are so many hidden compounds—we don’t know their structure and their use. In the soil, where the bacteria and the fungi live, there are also many hidden compounds. The ocean is full of organisms we have not explored. I’m sure that it is rich in new molecular structures which will come to our attention sooner or later. They will challenge synthetic chemists to invent new methodologies to synthesize these new types of structures.

I see a great future for the art and science of total synthesis. And, in addition to that, it is a great area to train graduate students and post-docs because it puts in front of them severe challenges in which they have to bring to bear all the tools of synthetic chemistry. They have to sharpen their minds and become practitioners in the art of making these molecules. There is a great need for this kind of training today—in fact, there is a shortage in manpower in this field. We do not have enough students and people in the industry will tell you the same thing.

What’s a typical project for graduate students?

Typical project? I can mention famous compounds like taxol, brevetoxin, vancomycin—these are very famous molecules—the CP molecules we have synthesized recently, or the epothilones which are extremely powerful anti-tumor agents. There are many. That’s what makes it so exciting, you see. The field is very vibrant, very exciting, and we are very fortunate to have a great number of talented students and post-docs here.

The practitioners of total synthesis exercise taste in selecting these targets. We look at the molecular architecture, [for] something that looks completely novel. Structures which I’ve seen for 25 years don’t excite me any more, but if I see something entirely new, unusual architecturally, then I’m attracted to it.

I also look for important biological activity in looking for a target. Taxol is an anti-cancer agent, vancomycin is an antibiotic. That’s an additional advantage because at the end of the road you know you are going to have a biological twist to your project. Combining chemistry and biology makes the project more worthwhile, more exciting, and more fulfilling for the student. They get training in both fields at the same time.

How do students deal with all the problems that can arise in a complicated, multiple-step synthesis?

Typically when they come into the group, we have discussions about the various projects that are ongoing. Sometimes they can join an ongoing project, [and] sometimes we pick new targets from the literature. Then we make a plan. I do encourage the students to participate in this planning, because that is a very important aspect of their education. We have to teach them how to think creatively and design their own synthetic strategies, because this is what is going to make them full and complete scientists who stand on their own feet. And that’s very attractive to them as well. They don’t want to be a pair of hands following the instructions of the professor. They want to be partners all the way from the beginning so they can exercise their creativity and sharpen their skills intellectually as well as experimentally.

There are many, many problems awaiting us along the path. We don’t worry about that. That’s a given, and we know that’s part of the excitement. We make as good a plan as we can, given the knowledge that we have, and don’t worry about the rest.

I tell the students, “Just get in the lab, we have a very good plan to follow, and things are going to crystallize sooner or later. Persist and withdraw when you are faced with difficulties, redesign the strategies, and try again.”

[In this field], you are going to fall on the ground many times. This practice requires stamina, requires character. It’s a real test of character, whether you can withstand these failures, one right after another. But that’s what makes a skillful professional. Whether it’s in business, in science, or in any endeavor. You have to be able to face difficulties and develop the abilities and methods to face these difficulties—to stand on your feet and try and try again. Sooner or later this seemingly unsolvable problem will melt in front of this human persistence and innovation.

And as you’re going along the path, you discover things that you never expected—completely by serendipity. Sometimes it’s like a hidden vein in the ground, which gives you gold or oil. [This vein] yields many things to figure out and explore. Of course, you have to be alert and astute to recognize an important discovery like this when it comes along.

Can you give me an example of such serendipitous discoveries?

Well, a very good example is one of our recent projects in the CP molecules. These CP molecules were really diabolical in their molecular architecture. They posed untold problems and challenges before they finally succumbed to the assault by the students who were involved. Along the way, we encountered an unexpected result, which did not help us solve the problem and yet gave us a gold mine of new synthetic methods to make heterocycling molecules. They are the ideal molecule for biological screening because they have the ability to bind to proteins. So out of that serendipitous discovery, which we made a couple of years ago, we probably have a dozen publications that describe new synthetic methodology that can be applied to combinatorial chemistry to give us compound libraries for biological evaluation.


Next Page | All Targets Old and New

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Some of the molecules that the Nicolaou lab has synthesized include vancomycin, CP-225,917, CP-263,114, epothilone A and B, brevetoxin A, and taxol.