John D. Roberts: The Seattle Veteran at NOS
Jun26

John D. Roberts: The Seattle Veteran at NOS

The Seattle conference welcomed chemists from near and far. They came from Berkeley, from Harvard, and from everywhere in between. Thirteen of the most eminent among them readied talks about their cutting-edge research, which they hoped would send everyone home inspired to further their own work. That meeting, the 16th National Organic Chemistry Symposium (NOS), took place fifty-four years ago. This week, the gathering is in its 43rd incarnation, and it's back in the Emerald City. So is one of the original speakers from that 1959 meeting-- John D. Roberts. As a young Caltech faculty member, Roberts gave a presentation entitled "Rearrangement Reactions of Small-Ring Compounds." It was already his third NOS talk, but he returned as a speaker several more times, collecting organic chemistry's highest honor, the Roger Adams Award, in 1967. Roberts, 95, is a pioneer in physical organic chemistry and nuclear magnetic resonance (J. Org. Chem. 2009, DOI: 10.1021/jo900641t). Conference cochair Paul B. Hopkins of the University of Washington made note of Roberts' presence during opening remarks. "I believe Professor Roberts is the only one of us in attendance who was also there at the 1959 Seattle NOS," Hopkins said, as the crowd gave Roberts an ovation. "But if I'm wrong about that, you'll have to let me know during the coffee break." Later that evening, this year's Roger Adams awardee, David A. Evans of Harvard, started his talk by thanking Roberts, who he called "inspirational," "my teacher," and "my friend of nearly 50 years." When Evans was a college student at Oberlin, the school "had just gotten an NMR, so we spent the summer poring over John's books" about the exciting new instrument, Evans recalled. He would get to know Roberts while earning his Ph.D. at Caltech. So Roberts could attend Evans' award lecture, NOS organizers broke with decades of tradition and moved the Adams Award Lecture, held on Tuesday nights for as long as anyone can remember, to Monday evening. Over a cup of black coffee, Roberts told C&EN about his experiences at NOS over the years. He reminisced about some of the scientific feuds that played out at the podium, including the epic cation controversy between Saul Winstein and H. C. Brown. Asked about the history of the meeting, recently published in the Journal of Organic Chemistry (DOI: 10.1021/jo302475j), which notes a decline in talks about his field of physical organic chemistry, Roberts is optimistic. "Physical organic is not dead--it's just been co-opted by everyone," he says. Problems in biochemistry, which might involve enzyme mechanisms or noncovalent interactions, are often very appealing to people trained in the field, he adds. The last time...

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Rigged Reactions: Biocatalysis Meets 13C NMR
Jul19

Rigged Reactions: Biocatalysis Meets 13C NMR

When you think of reaction screening, what comes to mind? Most would say LC-MS, the pharma workhorse, which shows changes in molecular polarity, mass, and purity with a single injection. Some reactions provide conversion clues, like evolved light or heat. In rare cases, we can hook up an in-line NMR analysis - proton (1H) usually works best due to its high natural abundance (99.9%). Please welcome a new screening technique: 13C NMR. How can that work, given the low, low natural abundance of ~1.1% Carbon-13? Researchers at UT-Southwestern Medical Center have the answer: rig the system. Jamie Rogers and John MacMillan report in JACS ASAP 13C-labeled versions of several common drug fragments, which they use to screen new biocatalyzed reactions. Biocatalysis = big business for the pharma world. The recent Codexis / Merck partnership for HCV drug boceprevir brought forth an enzyme capable of asymmetric amine oxidation. Directed evolution of an enzyme made sense here, since they knew their target structure, but what if we just want to see if microbes will alter our molecules? Enter the labeled substrates: the researchers remark that they provide an “unbiased approach to biocatalysis discovery.” They’re not looking to accelerate a certain reaction per se, but rather searching for any useful modifications using the 13C “detector” readout. One such labeled substrate, N-(13C)methylindole, shows proof-of-concept with their bacterial library, producing two different products (2-oxindole and 3-hydroxyindole) depending on the amount of oxygen dissolved in the broth. NMR autosamplers make reaction monitoring a snap, and in short order, the scientists show biotransformations of ten more indole substrates. This paper scratches multiple itches for various chem disciplines. Tracking single peaks to test reactions feels spookily close to 31P monitoring of metal-ligand catalysis. Organickers, no strangers to medicinally-relevant indole natural products, now have another stir-and-forget oxidation method. Biochemists will no doubt wish to tinker with each bacterial strain to improve conversion or expand scope. The real question will be how easily we can incorporate 13C labels into aromatic rings and carbon chains, which would greatly increase the overall...

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