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“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.” |
