Radical Synthesis of Natural Substances

Chemists have had a difficult time synthetically creating many important natural substances in the laboratory.

Bioactive compounds found in marine and terrestrial organisms often have anti-cancer, anti-bacterial and other desireable qualities. The cost of synthesizing the compounds can be prohibitive, though.

This is a critical concern, as identification of a reasonably economic means of production for marine and other natural products is typically one of the most challenging hurdles in a potential drug's commercial development. An overly complex and expensive synthesis can even slow or halt the development of an otherwise promising drug candidate.

....A range of drugs from aspirin to the widely used cancer treatment Taxol has been discovered in nature, but the complexity of producing natural products has made some companies reluctant to focus on them.

“There is this far-ranging and damaging perception that natural products are too complex to be used in a drug discovery setting despite their overwhelming track record in medicine,” says Baran. “I think if our work has helped in even a small way to revive the use of natural products, then we've served our purpose.”

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Phil Baran and colleagues at Scripps Institute have opened the door to faster and more economical synthesis of natural products by changing the rules.

A radically different approach to constructing complex molecules could help to tap the pharmaceutical potential of natural products. The concept, devised by Phil Baran and colleagues at Scripps Institute, La Jolla, California, promises to generate natural products in much larger amounts than conventional methods, making biological testing much easier for drug discovery scientists.

Most total syntheses, which assemble complicated carbon-based molecules from relatively simple building blocks, make liberal use of protecting groups. These chemical shields prevent completed parts of a molecule being altered while chemists are still tinkering with other sections that are still under construction. However, adding and removing protecting groups can add many steps to a synthesis, cutting overall yields drastically.

Baran's team have now made a collection of marine natural products without using a single protecting group. Instead, they take advantage of the intrinsic reactivity of the molecule's different functional groups.

This unconventional approach delivered several grams of compounds such as ambiguine and welwitindolinone in less than 10 steps. What's more, the reactions were enatioselective - they made only the preferred mirror-image form, or enantiomer, of the molecule, instead of a racemic mixture containing equal amounts of both enantiomers. This is a vast improvement over traditional syntheses, which make milligrams of racemic product in around 30 steps.

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