Meeting Delivers Organic Feast

More than 1,000 organic chemists gathered in Salt Lake City last month for the 39th Biennial National Organic Chemistry Symposium. As always, this year's symposium--held June 12-16 at the University of Utah's breathtaking, mountain-ringed campus--gave participants a taste of the diversity of problems being tackled by organic chemists.

First established in 1925, the National Organic Chemistry Symposium is sponsored by the American Chemical Society's Division of Organic Chemistry. In keeping with tradition, a special evening session honored the winner of the ACS Roger Adams Award in Organic Chemistry. The winner, celebrated organic chemist Jerrold Meinwald of Cornell University, reflected on how his lab extended the field of natural products chemistry to pioneer the discipline of chemical ecology (C&EN, Jan. 10, page 43).

The 2005 symposium, organized by Ahmed Abdel-Magid of Johnson & Johnson and Jon D. Rainier of the University of Utah, also featured more than a dozen invited lecturers and 440 posters. As the following highlights demonstrate, topics included the development of new chemical reactions and catalysts, the total synthesis of complex natural products, and the use of chemical synthesis to probe biological mechanisms.

C­H Amination Method Showcased

Organic chemists soon will begin to think of the C-H bond as a versatile synthon, if Justin Du Bois has his way. An associate professor of chemistry at Stanford University, Du Bois showed attendees how his group's novel C-H amination methods can be used to make not only ß-amino acids but also complex, nitrogen-rich natural products.

Previously, it was not realistic to consider C-H bond amination in the retrosynthetic planning of a complex target molecule, Du Bois noted. Earlier C-H amination methods involved capricious oxidants, were not stereoselective, worked only on simple hydrocarbons, and required a large excess of substrate.

By developing methods to selectively convert saturated C-H bonds to carbinolamine stereocenters, Du Bois and his students have made C-H amination more broadly useful. All that's needed is a simple dinuclear rhodium catalyst and a commodity oxidant to make a variety of nitrogen-containing heterocycles from inexpensive and easily prepared carbamate, sulfamate, urea, and sulfamide starting materials, Du Bois reported. Such heterocycles are readily converted into other value-added products.

The method can be used to prepare synthetically useful building blocks such as 1,3-diamines and ß-amino acids, Du Bois noted. "We also hope to use these methods to introduce C-N stereocenters in the late stages of multistep syntheses of complex natural products," he told C&EN. To be useful for natural product synthesis, amination must be directed to specific C-H centers in structurally intricate substrates. The Stanford team has achieved the necessary regioselectivity by modulating the architecture of the rhodium catalyst and by exploiting the differential reactivity of C-H centers.

To showcase the method, the Stanford team has used rhodium-catalyzed C-H amination to synthesize a variety of nitrogen-rich marine natural products, including tetrodotoxin (the blowfish toxin) and saxitoxin (an algal toxin found in contaminated shellfish). These molecules exert their toxic effects on humans by blocking the mouth of voltage-gated sodium channels. "Such compounds and related derivatives can serve as powerful tools for exploring the structure and function of sodium ion channels," Du Bois told C&EN.

"We hope that the popularity of C-H amination will increase as we work to boost our method's yields, flexibility, and stereoselectivity," he added. His lab recently has designed a new, more robust carboxylate-tethered rhodium catalyst that promotes the intermolecular amination of C-H bonds in high yield. Such intermolecular reactions offer an easy route to amine derivatives from off-the-shelf starting materials, Du Bois noted. His team is examining chiral versions of this optimized catalyst in the hopes of finding one capable of asymmetric C-H amination.

Siderophore Flips For Iron

For most bacteria--including pathogenic ones--iron is a limiting nutrient. To survive, pathogenic microbes must "steal" the iron they need from the host by secreting small, iron-binding organic molecules known as siderophores. John T. Groves, a bioorganic and bioinorganic chemistry professor at Princeton University, described how his lab has used organic chemistry to probe the function of the unusual and poorly characterized class of amphiphilic siderophores.

Amphiphilic siderophores feature both hydrophilic iron-chelating groups and lipophilic hydrocarbon chains that promote binding to cell membranes. A number of pathogenic bacteria, including Mycobacterium tuberculosis, produce such amphiphilic siderophores. "We wanted to know why it's important for these siderophores to bind membranes," Groves said.

His lab began by interrogating acinetoferrin, a citrate-based amphiphilic siderophore produced by the antibiotic-resistant strain Acinetobacter haemolyticus, a common cause of hospital-acquired bacterial infections. Tuberculosis-causing bacteria often intercept acinetoferrin to get the iron they need.

To probe the details of acinetoferrin function, Groves, graduate student Minkui Luo, and postdoc Evgeny A. Fadeev first developed methods to synthesize acinetoferrin as well as analogs with truncated or missing hydrocarbon tails. By studying the structure of a model gallium-bound acinetoferrin by nuclear magnetic resonance spectrometry, they found that the siderophore adopts an unusual extended conformation upon metal coordination, Groves noted. The Princeton team also has developed fluorescence- and NMR-based methods to probe the interaction of acinetoferrin with lipid membranes (J. Am. Chem. Soc. 2005, 127, 1726).

Upon invading its host, A. haemolyticus synthesizes acinetoferrin, Groves suggested. The amphiphilic siderophore eventually parks itself on the various intracellular membranes of the host cell. There, the siderophore waits to capture iron from iron-transporting proteins in the host. The dramatic shape shift triggered upon iron coordination causes the iron-loaded siderophore to pop out of the host membrane. Because iron-loaded acinetoferrin can more readily flip through lipid bilayers, it rapidly makes its way back to the outside of the pathogenic cell, where it's recaptured by special receptors.

More recently, Groves's team has turned its attention to the function of mycobactin, the amphiphilic siderophore produced by M. tuberculosis. These studies (Nat. Chem. Biol., published online July 3, dx.doi.org/10.1038/nchembio717) have identified a promising new target for tuberculosis drugs, he noted.

Spongistatin Synthesis Scaled Up

The marine natural product (+)-spongistatin 1 is, by all accounts, a highly promising anticancer drug candidate. But a chronic supply problem of this bis-spiroketal macrolide is hindering its clinical development. Amos B. Smith III, a chemistry professor at the University of Pennsylvania, described his lab's progress toward a synthetic fix for this supply problem.

Isolated from the marine sponge Hyrtios altum, (+)-spongistatin 1 "is the most potent anticancer cell-line inhibitor currently known," Smith noted. But the stuff is exceedingly scarce--a recent effort to reisolate (+)-spongistatin 1 required 13 tons of wet sponge to isolate just 35 mg of the natural product. Without a more plentiful supply, (+)-spongistatin 1 is unlikely to make it beyond early preclinical testing.

Smith reported that his lab now has in hand a synthetic route that he estimates can be used to make gram-scale quantities of the precious natural product. Such an achievement would open the door to further preclinical and biological testing of this compound.

The Smith lab's quest was inspired by the lab's prior successful completion of a gram-scale synthesis of another sponge natural product, (+)-discodermolide. The material provided by its synthesis furthered the biological and preclinical evaluation of the promising anticancer compound. Novartis later developed a 60-g-scale route based in part on the Smith synthesis, an achievement that made clinical testing of (+)-discodermolide possible.

"This gave us the courage to try to make gram quantities of (+)-spongistatin," Smith said. But (+)-spongistatin 1 is a far more complex molecule, and although several syntheses of (+)-spongistatin 1 have been reported, none has come close to providing a gram of material.

Smith described his lab's most recent and most promising route to (+)-spongistatin 1. The 30-step route--in which EF and ABCD fragments of (+)-spongistatin 1 are stitched together to furnish the complete natural product--has an overall yield of 2.2%. Thus far, this optimized synthesis has yielded 80 mg of (+)-spongistatin 1, more than the combined material from all previous isolation and synthetic efforts. The team has on hand enough material to prepare up to 1 g of (+)-spongistatin 1, Smith told C&EN.

Key to this scaled-up synthesis was the development of a multicomponent dithiane-coupling strategy that uses epoxides as electrophiles, Smith noted. This technique enables the rapid, stereoselective construction of orthogonally functionalized 1,5-diols, a feature shared by many advanced intermediates on the way to (+)-spongistatin 1. Another speaker, chemistry professor Steven V. Ley of Cambridge University, cited a similar dithiane-coupling strategy as crucial to his own synthesis of (+)-spongistatin 1.

Smith argued that recent scaled-up syntheses of (+)-discodermolide and now, (+)-spongistatin 1, make it clear that lengthy total syntheses of such complex natural products are no longer limited to delivering milligrams of product.