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PERSPECTIVE

The Tensions of Scientific Storytelling

Science depends on compelling narratives.

Roald Hoffmann

Synthesis of an Antitumor Agent

A prime example of a chemical narrative, no less striking today than when it was published 20 years ago, is the synthesis of paclitaxel, an effective and widely used antitumor drug. And a devilishly intricate molecule. In 1967, its activity in an extract from the bark of the slow-growing Pacific yew tree (Taxus brevifolia, hence the common chemical name taxol) was first noted by Monroe E. Wall and Mansukh C. Wani of the Research Triangle Institute. The tree takes hundreds of years to mature, and stripping off its bark kills it. To gain realistic use in therapy, taxol would have to be synthesized, or produced “semisynthetically” from a renewable precursor.

Competition to synthesize taxol in the laboratory was slow-paced in the beginning and sped up in the 1990s. In a photo finish with K. C. Nicolaou, then at the Scripps Research Institute, the group of Robert A. Holton of Florida State University was first. In early 1994, Holton’s group published two linked papers reporting the synthesis. The therapeutic motivation is stated in the first sentence of the first paper, as is the challenge the molecule’s baroque structure presents: “The total synthesis of … taxol … has stood for over 20 years as a major challenge for organic chemists.”

2014-07PerspectiveHoffmannFp252.jpgClick to Enlarge ImageNote the establishment of narrative tension—organic chemists had tried before to make taxol and failed to do so. The drawing labeled 1 in the figure at right shows the molecule. Note also the usual organic nomenclature in the molecule’s depiction—a vertex of a polygon is assumed to be a carbon, and the hydrogens attached to it are omitted, but their number is evident if one recognizes that the valence of carbon is normally four.

The authors then voice, modestly but directly, the principal author’s stake in the taxol synthesis:

Until now, our taxane research program has produced a synthesis of the taxane ring system, a total synthesis of taxusin, and a (now commercialized) semisynthesis of taxol.

Presently, the complete synthesis reported in this paper in 1994, a magnificent intellectual achievement, is not used commercially. A “semisynthetic” process, starting with ground-up, farmed ornamental yews, is more efficient. These contain a molecule with most of taxol’s complexity, but lacking the tail at left in 1. The attachment of that tail is covered in a patent referenced in a footnote to the above sentence. That patent, for what seems to be a small piece of the making of a useful molecule, has brought in more than $200 million to Florida State.

Next, Holton and his 17 coworkers get to work:

Thus, our route to taxol proceeds retrosynthetically through C-7 protected baccatin III (2) to the tricyclic ketone 3, which arises from C ring closure of a precursor 4.

The jargon—names of molecules and shorthand for reactions—deals outsiders out, as all jargon does, but nevertheless is assuredly in the toolkit of the readership of this paper.

The word retrosynthetic is key (introduced by the great organic chemist, E. J. Corey of Harvard University): It refers to the structure sequence 1 2 3 4 5 shown in the figure above. The thick arrows here mean in plain English “will be derived from,” and the sequence shows conceptual unstitching of the carbon skeleton, progressing from complexity to relative simplicity. The synthetic path the authors contemplate is thus the reverse of this sequence, 5 → 4 → 3 → 2 → 1, where the thin arrows mean “turns into”; it takes many physical steps to achieve each transformation. The beginning, molecule 5, is not as ubiquitous as earth, air, fire, or water, but it is easily available from an abundant natural product, camphor. The actual synthesis, with experimental detail, begins later in the paper. The process takes 37 steps.

Where’s the story here? Well, it’s less of a whodunit and more of a “how-the-heck-did-they-do-it”—in a way, an ultimate demonstration that it is the path that matters. This approach is much like a classic quest narrative. The path is set out in the retrosynthetic chain in the figure on page 252. Chemical “Laistrygonians and Cyclops, angry Poseidon” were along the way; they were overcome or evaded. Will the 18 authors of this paper achieve their goal; will Odysseus reach his Ithaka? They did. And the makers probably would have set out the story—yes, the story—quite differently had this road map failed them.

Note the dual protagonist of this tale: the molecule to be sure, and the chemists who made it. Is not the retrosynthetic scheme, the plan set out to make the molecule, a glimpse into the inner life of the molecule? Or is it the inner thinking of the narrator chemists? Remarkably, the molecule has still another life, another story to tell, one that is not revealed in this paper. It is the way taxol is made, naturally, in the Pacific yew. You can be sure that it isn’t the way that Holton’s group made it. There are six more stories to be told, in the ingenious other syntheses of the molecule.

This paper tells how a much-desired molecule was made for the first time in the laboratory. All the elements of a heroic epic are there—a quest, and in the parts of the paper not shown, battles with the elements, obstacles galore that must be overcome, and in the end, deserved success—with perhaps the exception that the journal article lacks an explicit rendering of the synthetic chemists’ thoughts. But there is enough detail in the story that readers can imagine what the makers felt. One lovely, complex, and useful molecule—breeding a multitude of stories.








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