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An Abundance Of Organic Chemistry

Meeting spotlights diverse interests of organic chemists, including biological and catalytic systems

by Bethany Halford
July 2, 2007 | A version of this story appeared in Volume 85, Issue 27

A Long Hop
The proposed 35-Å pathway of proton-coupled electron transfer from region R2 to region R1 in ribonucleotide reductase.
The proposed 35-Å pathway of proton-coupled electron transfer from region R2 to region R1 in ribonucleotide reductase.

EVER SINCE its humble beginnings in 1925, the National Organic Chemistry Symposium, or NOS as it's known among organic chemists, has had a reputation for bringing top-notch organic chemists together in a convivial atmosphere. The 900 or so chemists who gathered last month for the 40th NOS—held June 3–7 at stately Duke University—continued that tradition into its ninth decade.

The meeting, sponsored biennially by the American Chemical Society's Division of Organic Chemistry, also honors the winner of the ACS Roger Adams Award in Organic Chemistry with a special evening session. This year's winner, famed synthetic organic chemist Samuel J. Danishefsky of Columbia University and Memorial Sloan-Kettering Cancer Institute, said that it was "through the magic of America and the magic of science" that he had been able to achieve such success.

Not everything at NOS was bound by tradition, however. Hosts P. Andrew Evans, from England's University of Liverpool, and Ross A. Widenhoefer, from Duke, told C&EN that they made a conscious effort to broaden the program beyond organic chemistry's traditional boundaries.

"NOS is about setting a new paradigm for science and highlighting people who are truly leading in the field," Evans said. The meeting's lineup of 13 plenary speakers and more than 350 poster presentations included mainstay topics such as total synthesis, catalysis, and methods development and also reached into the realms of biochemistry and nanotechnology. Here are some highlights from the meeting.

A Radical Goes the Distance

Thirty-five angstroms may not seem like a great distance, but from JoAnne Stubbe's point of view, it's a veritable gulf. That's because Stubbe, a professor at Massachusetts Institute of Technology, is trying to figure out how a tyrosyl radical in the ribonucleotide reductase enzyme propagates across 35 Å to generate a cysteinyl radical, which catalyzes the conversion of nucleotides to deoxynucleotides—an essential step in DNA replication and repair.

Electron transfer across 35 Å in the absence of metals is completely unprecedented in biology, Stubbe said. "Electron transfer occurs very frequently in biological systems, like in nitrogen fixation or photosynthesis or respiration. But in general, it occurs between metal centers, and the distance between metal centers is usually 10 to 15 Å," she explained.

Ribonucleotide reductase consists of two subunits—R1, where the active site is, and R2, where the initial tyrosyl radical is generated. Scientists believe that for the radical to traverse the distance between the two subunits, proton-coupled electron transfer (concerted transfer of an electron and a proton) occurs along a pathway that involves several amino acid radical intermediates. These intermediates include a tryptophan and tyrosine in the R2 region and two other tyrosines in the R1 region.

To investigate how the radical "hops" between tyrosine residues, Stubbe and her MIT collaborator Daniel G. Nocera developed a series of fluorinated tyrosine analogs. With regard to size, these nonnatural amino acids are similar to tyrosine, but they have a broad pKa and reduction potential range, depending on the number of fluorine atoms on tyrosine's phenol ring (J. Am. Chem. Soc. 2006, 128, 1569).

In the natural enzyme, the rate-limiting step is a conformational change in the enzyme. Stubbe and Nocera's team hypothesized that by replacing one of the tyrosines with a fluorinated analog, they could shift the reduction potential so that electron transfer to that tyrosine would be the rate-limiting step. This would allow them to determine whether that tyrosine is involved in the radical propagation pathway.

"Most biological systems are conformationally gated," Stubbe noted. To study the effect of an individual residue, she explained, you have to perturb the system. "You have to shift the system so what you're interested in is rate limiting, to see an effect," she said.

Indeed, that's precisely what happened when the group made the enzyme with the fluorinated tyrosine analog in place of a specific tyrosine residue in R2 (J. Am. Chem. Soc. 2006, 128, 1562). "Nobody knew what the reduction potential of these fluorinated analogs would be relative to tyrosine," Stubbe said. "I think we were exceedingly lucky that they turned out to be right in the range where it turned out to have a pretty dramatic biological effect."

Proving that the proton-coupled electron transfer takes place along the proposed pathway has several implications, Stubbe pointed out. Therapeutically, it suggests that drugs that are known to destroy the tyrosyl radical in ribonucleotide reductase—the chemotherapeutic agent hydroxyurea, for example—aren't necessarily working on the initial tyrosyl radical, which is buried deep within the enzyme. Instead, it may be interfering with one of the tyrosyl radicals along the electron-transfer pathway.

Although this type of hopping mechanism has been observed in biological molecules such as DNA, this is the first time it's been demonstrated to be important in proteins in vivo. Furthermore, Stubbe said, the mechanism may play a greater role in electron-transfer reactions in biological systems than has heretofore been realized.

Toward the Architecture of Acutumine


Zipped Up
The key step in constructing acutumine's architecture makes use of a sequence of carbonyl-dependent reactions. The final steps (indicated by the dashed arrow) have yet to be completed.

From a medicinal point of view, the alkaloid acutumine has a few things going for it. The compound inhibits human T-cell growth at low micromolar potency and has been shown to enhance memory in animal studies. To Princeton University chemistry professor Erik J. Sorensen and graduate student Robert J. Moreau, though, the most appealing thing about the molecule was the opportunity it presented for constructing a complex chemical architecture in just a few steps (Tetrahedron 2007, 63, 6446).

Acutumine is a relatively small molecule, but what it lacks in size it makes up with complexity. Its central core features a propellane-like [] fused tricycle with a spirocycle appendage. The compound contains five contiguous stereocenters, three of which are fully substituted.

"We were drawn to its complex cyclic connectivity," Sorensen told C&EN. "It has the type of topology that you don't often encounter in the realm of natural products."

For their synthesis, Sorensen and Moreau decided to make the pyrrolidine ring the core element. By doing so, they could use carbenoid insertion chemistry to easily access the keto proline ester that would be their basic building block.

After appending key functionalities to the core pyrrolidine, they reasoned they could make the tricyclic core via an intramolecular rearrangement of a bicyclic vinylogous carbonate in the presence of base. The transformation relies upon a sequence of carbonyl-dependent reactions—a workhorse of organic chemistry.

First, addition of base leads to a β-elimination that opens the carbonate ring, leaving behind an enolate ion and an electrophilic enone. The subsequent intramolecular Michael addition zips up two of the fused rings at the molecule's core. The third fused ring of the tricyclic architecture arises from a Dieckmann-like cyclization.

Sorensen and Moreau were able to induce the entire sequence in the presence of strong, nonnucleophilic bases, but they found that the reaction went more cleanly if it was carried out in two steps. Overall, they were able to achieve the compound's challenging core architecture in just seven steps.

The total synthesis of acutumine is still a work in progress, Sorensen said, but the ultimate goal, as always, is to finish the molecule in as few steps as possible. The ideal synthesis, Sorensen explained—the one that he considers a benchmark for all the synthetic work in his lab—was originally described by Stanford University's Paul A. Wender: "Making complex molecules from simple starting materials in one step and 100% yield in a manner that is operationally simple, fast, safe, environmentally acceptable, and resource efficacious."

Mining the Main Group for New Catalytic Reactions

When it comes to choosing a catalyst, chemistry professor Scott E. Denmark of the University of Illinois, Urbana-Champaign, thinks chemists are too hung up on transition metals. Venture toward the periodic table's main group, he contends, and there are plenty of opportunities for finding new catalytic processes.

"In the field of catalysis, the focus has been primarily on the transition metals and also on the use of Lewis acid and protic catalysis," Denmark explained. "But if you think of the breadth of interesting chemistry that exists in the main group between lithium and iodine, there's a phenomenal amount of interesting chemistry, very little of which has been rendered catalytic, let alone enantioselective."

To tap into those unmined opportunities, Denmark has been exploring Lewis base catalysis. In a Lewis-base-catalyzed reaction, an electron-pair donor acts upon an electron-pair acceptor and thereby accelerates a chemical transformation. "The fascinating thing about Lewis base catalysis is that it can operate by enhancing both the electrophilic reactivity and the nucleophilic reactivity of a substrate," Denmark said.

That a Lewis base can increase a Lewis acid's electrophilicity runs contrary to the popular assumption that complexation decreases a Lewis acid's electropositive nature. Calculations show that when a Lewis acid complexes with a Lewis base, the core atom in the Lewis acid actually can become more electropositive.

In the series SiCl4, SiCl5-, SiCl62-, for example, the charge on the silicon atom increases from +0.178 to +0.279 to +0.539 with the addition of each chloride ion. So even though SiCl62- carries a double negative charge, its electron-pair acceptor, the silicon atom, has an increased positive charge in comparison with the neutral SiCl4 species.

The upshot is that a Lewis base catalyst can make a poor Lewis acid, such as SiCl4, more electrophilic. Using a chiral Lewis base, such as a chiral bis-phosphoramide, can lead to reactions that are enantioselective. Denmark's group has used this strategy for a number of asymmetric reactions: aldol additions, allylations of aldehydes with stannanes, and epoxide openings, to name a few.

Although Denmark has done a substantial amount of work on the SiCl4 system, he pointed out that the concept applies for many main-group elements. "The idea was to show the principle behind the activation of a weak electrophile with a Lewis base to make a strong electrophile," Denmark said. He added that much of the interesting chemistry in the main group???the chemistry of sulfur, selenium, iodine, and bromine???is effectively electrophilic chemistry, which makes it ripe for Lewis base catalysis. Denmark's review on the topic will appear in an upcoming issue of Angewandte Chemie.


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