Chemist Phil Baran has turned the organic chemistry world on its head by rejecting a long held maxim of chemical synthesis. With the help of the Scripps Research Institute, his team proved they were able to make grams of compounds in fewer steps than are typically needed to make milligrams of product.
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.