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Process Chemistry

Turning lignin into bioactive molecules in three green steps

Efficient, waste-free process transforms pine wood into novel benzazepines

by Louisa Dalton, special to C&EN
October 14, 2019


Reaction scheme showing lignin undergoing mild depolymerization to yield dihydroconiferyl alcohol, which then undergoes a two-step synthesis to yield various benzazepine derivatives.
Credit: Adapted from ACS Cent. Sci.
A green route turns lignin from pine wood into biologically active benzazepine derivatives, which could lead to new drugs.

Lignin—a tough, mixed polymer found in plant cell walls—is nature’s most abundant stockpile of aromatic functional groups. Because of this, lignin’s rich natural complexity could be a well of new bioactive molecules for potential drugs, but the polymer’s complexity makes it difficult to break up into usable chunks. Now, scientists have built upon recent lignin depolymerization methods to introduce a green, efficient, three-step pathway from lignin to bioactive compounds that can be turned into drugs (ACS Cent. Sci. 2019, DOI: 10.1021/acscentsci.9b00781).

Lignin’s carbon-carbon and ether bonds are strong and can’t be hydrolyzed, which makes plant cell walls durable and impermeable to water. They also make pulling lignin apart into usable monomers a little like extracting whole tiles from the bathroom wall—it’s hard to keep them intact. Over the last 10 years, however, chemists have tackled the lignin breakdown problem, describing a number of viable depolymerization methods. For example, Katalin Barta’s group at the University of Groningen can convert lignocellulose—a plant fiber’s intertwined matrix of lignin and cellulose—to a crude, but usable, mixture of different lignin monomers, oligomers, and plant sugars (Nat. Catal. 2018, DOI: 10.1038/s41929-017-0007-z).

The next challenge, Barta says, is to pluck out certain monomers and create pathways to valuable compounds. Other groups have focused on converting lignin into new polymers or bulk chemicals, but Barta saw a path to potential pharmaceuticals. “Nature has provided basically half of the medicine already,” she says, which could lead to efficient, cost-effective ways to synthesize drugs.

Lignin in pine, Barta found, yields high amounts of a particularly interesting monomer, dihydroconiferyl alcohol, which sports a three-carbon aliphatic alcohol. She envisioned those three carbons as the core of a new seven-membered ring found within bioactive compounds called benzazepines. Alzheimer’s disease and high blood pressure are both targeted by current benzazepine drugs.

Barta’s group first designed a selective amination reaction. Within the crude mixture, they convert the alcohol into an amine with the help of a ruthenium catalyst, skipping the need to isolate the alcohol. They show this step can work selectively on dozens of starting amines to produce an array of aminated lignin offshoots.

To avoid organic solvents, Barta’s group then cyclized the amines in a biodegradable deep eutectic solvent consisting of choline chloride and oxalic acid. The combination improved selectivity and ring formation efficiency. What they ended up with are three spare steps from lignocellulose to a library of benzazepines, with water as the only by-product.

A number of the resulting novel benzazepines were bioactive. Of the 41 tested, 14 inhibited growth of cultured human cancer cells. Five killed Staphylococcus aureus bacteria. Barta is now optimizing the most promising compounds’ activity and tweaking their green synthesis to produce a range of new and existing drugs. “This modular synthetic pathway gives us plenty of room to play with,” she says.

Catalysis expert Shannon S. Stahl of the University of Wisconsin–Madison says that producing bioactive compounds from lignin without large amounts of waste is very challenging, and he applauds the creativity of Barta’s approach.

Lignin biorefining can be expensive. The ability to produce high-price compounds like pharmaceuticals from lignin could make a small-scale process profitable, adds Jeremy Luterbacher, who works on green chemistry and biomass conversion at the Swiss Federal Institute of Technology, Lausanne. Before lignin can become a renewable feedstock for bulk chemicals, he says, “I think it needs a stepping stone like this.”


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