http://www.eurekalert.org/pub_releases/2007-03/sri-spo032107.php

Synthetic production of potential pharmaceuticals dramatically
simplified by Scripps research team

Findings could expand interest in natural products by making production
more cost-effective

Chemists are currently able to synthetically produce almost any
compound, but they must typically resort to expensive, complex processes
that can require dozens of individual steps. Such natural product
syntheses have traditionally relied on the ubiquitous use of "protecting
groups," which are extra compounds chemists use to shield reactive
portions of a molecule during specific stages of a synthesis scheme. The
protecting groups are eventually cleaved chemically to expose the
reactive portion during later chemical reactions to complete a product's
synthesis. Each protecting group used adds at least two steps to a
synthesis, and the groups themselves have reactivity of their own that
must be controlled to prevent adverse reactions.

"Protecting groups are almost always a direct result of an inability to
address selectivity in synthesis," says project leader Phil Baran, a
chemist with The Scripps Research Institute. "It is ironic that they
often add an additional layer of problems on top of the preexisting
ones."

Organic chemistry textbooks have long declared that the use of
protecting groups was essential in natural product synthesis. "Textbooks
have pointed out that avoiding protecting groups is like 'avoiding death
and taxes,'" says Baran, who, along with Scripps Research Kellogg School
of Science and Technology graduate students Thomas Maimone and Jeremy
Richter, has now disproved the belief.

To avoid the need for protecting groups, the Baran group took an
unorthodox approach. Rather than assume that reactive portions of a
molecule had to be shielded during various syntheses, the researchers
calculated ways to use such reactivity in an overall scheme to produce
the desired final product. Baran says the reason such an approach had
not been successfully developed before was likely a by-product of
education. "From the beginning, we were always taught that the way to
solve these types of problems is to protect functionality rather than to
try to embrace it," he says.

In the Nature paper, the group showed that, without using a single
protecting group, they could produce the representative members of a
whole family of over 60 different marine natural products produced by
the Stigonemataceae family of cyanobacteria. This family of products has
a wide range of bioactivities including anticancer and antibacterial,
and some may eventually be developed as commercial pharmaceutical
products. The compound family was only used as an example, however, as
the demonstrated concepts and principles should be applicable to the
synthesis of a wide range of marine and terrestrial natural products.

To synthesize the products, the team designed a variety of chemical
reactions that maximize the bonding of carbon atoms between different
molecules. In many cases, the products were synthesized in gram
quantities in less than 10 steps, as compared to traditional syntheses
using protecting groups that have taken as many as 30 steps to produce
milligrams of product.

Use of the techniques the group has developed could therefore lead to
substantially reduced production costs for natural products. 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.

Beyond economic ramifications, Baran hopes the research will offer
additional benefits to the drug discovery field. Many pharmaceutical
companies' potential drug pipelines are drying up, leading some to
suggest that interest in natural products should be renewed. 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."

The Baran team has focused its work to date on marine natural products,
because these chemical compounds from sponges, algae, and other
organisms have proven a rich source of bioactivity with pharmaceutical
potential, but have also been challenging to work with. Marine natural
products are ideal targets for simplified synthesis techniques because
they tend to be exceptionally complex, and because they are typically
difficult to collect. Researchers often struggle to amass marine
organism samples in quantities great enough to yield the volume of a
given compound needed for research and clinical trials, much less
commercial production, making better and cheaper production means all
the more critical.

For the production of some products, both natural and man-made, the use
of protecting groups will still be the most efficient route, says Baran.
"We are not advocating that one should blindly throw away the protecting
groups book just for the fun of throwing it away," he says. "It's
something that should be strategically applied."

###

Baran, Maimone, and Richter were all authors on the study, "Total
Synthesis of Marine Natural Products Without Using Protecting Groups."

This work was supported by The Scripps Research Institute, Amgen,
AstraZeneca, the Beckman Foundation, Bristol-Myers Squibb, DuPont, Eli
Lilly, GlaxoSmithKline, Pfizer, Roche, the Searle Scholarship Fund, the
Sloan Foundation, the National Science Foundation, and the National
Institutes of Health.

The research is being published on March 22, 2007 in the journal Nature.