Fig. 1: Chemical structure of the natural product haplophytine, derived from the ancient Aztec plant Haplophyton cimicidum.
Graphic © 2009 K. C. Nicolaou, Scripps Research Institute; Photograph © 2009 Elizabeth Makings, ASU Herbarium, Southwest Biodiversity Consortium
From the bottom of the ocean floor to the rainforests of Madagascar, scientists are on the hunt for natural products—diverse chemical compounds derived from plants, micro-organisms and animals. Some of history’s most successful pharmaceutical medications have been produced or inspired by the intricate molecular architectures of natural products, many of which can only be generated biologically.
When chemists accomplish a total synthesis—completely create a natural product from smaller and simpler molecules—it marks a major achievement. Often, new synthetic strategies must be developed to emulate nature’s handiwork. Now, with the total synthesis of the natural product haplophytine (Fig. 1), the team of K. C. Nicolaou, David Chen and co-workers from the Institute of Chemical and Engineering Sciences of A*STAR, Singapore, has fulfilled a decades-long quest.
First isolated from the wild Mexican plant Haplophyton cimicidum 57 years ago, haplophytine has been used since Aztec times as a natural insecticide. Its complex chemical framework features ten rings, unusual functionalities and multiple asymmetric centers that are notoriously difficult to construct. According to Chen, this challenging molecular structure has made haplophytine stand out as a target to total synthesis chemists.
Beginning with a small two-ring system, the researchers gradually added a third ring using an asymmetric ruthenium catalyst. They then faced the most challenging aspect of the total synthesis: forming a crowded carbon–carbon bond that joins the left- and right-hand sides of haplophytine together. At this point, they discovered that hypervalent iodine, a highly oxidizing reagent, produced a new six-ring intermediate containing the congested bond.
The researchers then used an innovative internal skeletal rearrangement, induced by a peroxide–carboxylic acid, to generate the left-hand-side domain of haplophytine. An extensive search revealed that unique reagents such as thallium ethoxide were needed to couple the final carbon fragments onto the molecule. A free radical cyclization, followed by an iron cyanide treatment, finally yielded the haplophytine structure.
Overall, the total synthesis required 33 steps. With an average yield of 73% per step, the final product yield was 0.035%—a figure that exemplifies how difficult it is to create complex natural products from scratch. Fortunately, organic chemistry has a long history of idea sharing that makes advances, such as the synthesis of new biological-related drugs, possible.
“Each successful synthetic transformation was an individual accomplishment,” says Chen. “Overcoming the obstacles in the haplophytine campaign goes far beyond our group’s achievement—it stands as a true testament to the power of modern organic synthesis.”
The A*STAR-affiliated authors in this highlight are from the Institute of Chemical and Engineering Sciences.
