SCIENCE & TECHNOLOGY

MEETING DELIVERS ORGANIC FEAST Biennial symposium highlights rich diversity of problems that organic chemists can help solve

O R G A N I C C H E M I S T R Y

MORE THAN Ι,ΟΟΟ ORGANIC chemists gathered in Salt Lake City last month for the 39th Biennial National Or­ganic Chemistry Sympo­

sium. 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.

C-H 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 β-amino acids but also complex, nitrogen-rich natural products.

Previously, it was not realistic to consid­er C-H bond amination in the retrosyn-thetic planning of a complex target mole-

cule, 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 carbinol-amine 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 β-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 Τ 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 am-phiphilic 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

ENABLER C-H amination can be used to make |>-amino acids from alcohols

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siderophores to bind membranes," Groves said.

His lab began by interrogating acin-etoferrin, a citrate-based amphiphilic siderophore produced by the antibiotic-resistant strain Acmetobacterhaemolyticus, 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

SHAPE SHIFT Acinetoferrin (carbon is dark blue; oxygen, red; and hydrogen, light blue) undergoes a dramatic conformational change upon binding iron (yellow).

acinetoferrin with lipid membranes (J.Am. Chem. Soc. 2005,127,1726).

Upon invading its host, A. haemolyticus synthesizes acinetoferrin, Groves sug­

gested. 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 (+)-spongi-statin 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 currendy 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. No-vartis 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 (+)-spongi-statin 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 toldC&EN.

Key to this scaled-up synthesis was the development of a multicomponent dithi-ane-coupling strategy that uses epoxides as electrophiles, Smith noted. This tech­

nique enables the rapid, stereoselective construction of orthogonally functional-ized 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. •

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