Retro Synthetic Analysis, or Is Nature Perfect?


The gods of the earth and sea
Sought through nature to find this tree,
But their search was all in vain:
There grows one in the human Brain.

—From The Poems of William Blake


By Jason Socrates Bardi

Finding chemicals with biologically useful properties has become the stuff of modern day legends. Compounds that exhibit anti-tumor activity, viral replication inhibitor molecules, thermally stable enzymes, and other holy grails that achieve biological goals have been found in nature.

And so from the Pacific yew groves to the deep sea vents, we quest after these undiscovered, potentially useful compounds. Any tree, toad, or random gram of terra firma could contain the next ibuprophen or AZT. Once found, these compounds can be studied, solved, synthesized, and mass produced—to the benefit of all mankind.

Nature provides and science supplies.

But uncovering nature’s secret compounds and finding ways to synthesize them is only the beginning. A basic science laboratory is interested in not only what we can get from nature, but what we can learn from it.

“There is this impression that if it comes from nature, then we can’t do any better,” says Dale Boger, who is the Richard and Alice Cramer Professor of Chemistry at The Scripps Research Institute (TSRI). "But in fact, nature rarely makes the molecules for the reasons that we find them useful or interesting."

Because the compounds we discover may not have evolved to do exactly what we want them to do, we cannot expect to find the best agents in nature. However, what we can expect to find are lead compounds from which we can gain insight into the design of others.

Boger calls this "constructionist science"—the synthesis of function, not solely the synthesis of molecules. And he and his colleagues at TSRI seek to use the tools of organic synthesis to identify, imitate, understand, exploit, and sometimes surpass what nature provides.

A Problem in Search of its Chemistry

The science starts, of course, with synthesizing compounds that exist in nature. "We’re a group that chooses its synthetic targets based on the properties of the molecules," Boger says, "And a large proportion of our targets have a unique mechanism or properties associated with them that make them interesting in their own right."

Boger and his colleagues use the technique known as retro synthetic analysis, where a scientist looks at a structure, moves back one step to a precursor of this structure, and then thinks of a way to convert that precursor to the final product. There are usually multiple possible precursors, and each of these will have several precursors that could be used to form them.

A path must be chosen, and the selection usually reflects the personality, expertise, and the interests of the chemist. "If you have a hundred chemists, you’ll have a hundred different routes to the final molecule," says Boger.

After synthesizing an interesting natural product, further investigations can show what it is about the compound and its interaction with its biological target that makes it active, and this information can then be used to make simpler or better agents.

This type of work is time-consuming. A novel synthesis may require as many as 40 steps, each step being a reaction in which a molecule a little closer to the target is formed. Some steps may be easy to anticipate beforehand, and others may have to be invented from scratch, and each step may require 10 to 20 novel approaches before finding one that works well. Each approach may have to be repeated several times, and each time various analytical tools have to be used to determine the reaction product and yield. Then there may be 10 to 20 optimizations at each step as well.

Boger estimates his laboratory spends about 90 percent of its time tackling various syntheses. And a project may take several years from start to finish.

"It’s not something that you can make today and analyze tomorrow," says Boger.

Next Page | Working with tumor-supressing compounds

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“There are structures that we are working on today that 10 or 12 years ago would not have been considered realistic to prepare in the laboratory. And other things you can do today with 10, 20, or 1,000 times less material than it would have taken a decade ago.”