SCIENCE & TECHNOLOGY The Stanford team has achieved the nec essary 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 nitro gen-rich marine natural products, includ ing tetrodotoxin (the blowfish toxin) and saxitoxin (an algal toxin found in contam inated shellfish). These molecules exert their toxic effects on humans by blocking AMANDA YARNELL, C&EN WASHINGTON the mouth of voltage-gated sodium chan nels. "Such compounds and related deriv ORE THAN Ι,ΟΟΟ ORGANIC Previously, it was not realistic to consid atives can serve as powerful tools for ex chemists gathered in Salt er C - H bond amination in the retrosynploring the structure and function of Lake City last month for the thetic planning of a complex target molesodium ion channels," Du 39th Biennial National Or Bois told C&EN. ganic Chemistry Sympo ENABLER sium. As always, this year's symposium— "We hope that the popu C-H amination can be used to make |>-amino heldJune 12-16 at the University of Utah's larity of C - H amination will acids from alcohols breathtaking, mountain-ringed campus— increase as we work to boost gave participants a taste of the diversity our method's yields, flexibil of problems being tackled by organic ity, and stereoselectivity," he chemists. added. His lab recently has designed a new, more robust First established in 1925, the National carboxylate-tethered rhodi Organic Chemistry Symposium is spon um catalyst that promotes sored by the American Chemical Society's the intermolecular amina Division of Organic Chemistry In keeping tion of C - H bonds in high with tradition, a special evening session yield. Such intermolecular re honored the winner of the ACS Roger actions offer an easy route to Adams Award in Organic Chemistry The amine derivatives from offwinner, celebrated organic chemistJerrold the-shelf starting materials, Meinwald of Cornell University, reflected Du Bois noted. His team is on how his lab extended the field of natu examining chiral versions of this optimized ral products chemistry to pioneer the dis cule, Du Bois noted. Earlier C-H amination catalyst in the hopes of finding one capa cipline of chemical ecology (C&EN, Jan. methods involved capricious oxidants, were ble of asymmetric C - H amination. 10, page 43). not stereoselective, worked only on simple hydrocarbons, and required a large excess The 2005 symposium, organized by of substrate. Ahmed Abdel-Magid of Johnson & John son andJon D. Rainier of the University of By developing methods to selectively Utah, also featured more than a dozen in convert saturated C - H bonds to carbinolamine stereocenters, Du Bois and his stu vited lecturers and 440 posters. As the fol dents have made C - H amination more For most bacteria—including pathogenic lowing highlights demonstrate, topics in ones—iron is a limiting nutrient. To sur broadly useful. All that's needed is a simple cluded the development of new chemical dinuclear rhodium catalyst and a com vive, pathogenic microbes must "steal" the reactions and catalysts, the total synthesis modity oxidant to make a variety of nitro iron they need from the host by secreting of complex natural products, and the use gen-containing heterocycles from inex small, iron-binding organic molecules of chemical synthesis to probe biological pensive and easily prepared carbamate, known as siderophores. John Τ Groves, a mechanisms. sulfamate, urea, and sulfamide starting ma bioorganic and bioinorganic chemistry terials, Du Bois reported. Such heterocy professor at Princeton University, de cles are readily converted into other valuescribed how his lab has used organic chem added products. istry to probe the function of the unusual and poorly characterized class of amThe method can be used to prepare syn phiphilic siderophores. Organic chemists soon will begin to think thetically useful building blocks such as Amphiphilic siderophores feature both of the C - H bond as a versatile synthon, if 1,3-diamines and β-amino acids, Du Bois hydrophilic iron-chelating groups and Justin Du Bois has his way. An associate noted. "We also hope to use these meth lipophilic hydrocarbon chains that pro professor of chemistry at Stanford Uni ods to introduce C - N stereocenters in the mote binding to cell membranes. A num versity, Du Bois showed attendees how his late stages of multistep syntheses of com ber of pathogenic bacteria, including My group's novel C - H amination methods can plex natural products," he told C&EN. To cobacterium tuberculosis, produce such be used to make not only β-amino acids be useful for natural product synthesis, am amphiphilic siderophores. "We wanted but also complex, nitrogen-rich natural ination must be directed to specific C - H to know why it's important for these products. centers in structurally intricate substrates.
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Biennial symposium highlights rich diversity of problems that organic chemists can help solve
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Siderophore Flips For Iron
C-H Amination Method Showcased
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siderophores to bind membranes," Groves said. His lab began by interrogating acinetoferrin, a citrate-based amphiphilic siderophore produced by the antibioticresistant 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 NMRbased 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 sugWWW.CEN-0NLINE.ORG
the promising anticancer compound. Nogested. The amphiphilic siderophore evenvartis later developed a 60-g-scale route tually parks itself on the various intracelbased in part on the Smith synthesis, an lular membranes of the host cell. There, achievement that made clinical testing of the siderophore waits to capture iron from (+)-discodermolide possible. iron-transporting proteins in the host. The "This gave us the courage to try to make dramatic shape shift triggered upon iron gram quantities of (+)-spongistatin," Smith coordination causes the iron-loaded said. But (+)-spongistatin 1 is a far more siderophore to pop out of the host memcomplex molecule, and although several brane. Because iron-loaded acinetoferrin syntheses of (+)-spongistatin 1 have been can more readily flip through lipid bilayers, reported, none has come close to providit rapidly makes its way back to the outside ing a gram of material. of the pathogenic cell, where it's recapSmith described his lab's most recent tured by special receptors. and most promising route to (+)-spongiMore recently Groves's team has turned statin 1. The 30-step route—in which EF its attention to the function of mycobactin, and ABCD fragments of (+)-spongistatin the amphiphilic siderophore produced by M. tuberculosis. These studies (Nat. Chem. 1 are stitched together to furnish the comBiol., published online July 3, dx.doi.org/ plete natural product—has an overall yield of 2.2%. Thus far, this optimized synthe10.1038/nchembio717) have identified a sis has yielded 80 mg of (+)-spongistatin 1, promising new target for tuberculosis more than the combined material from all drugs, he noted. 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 dithiThe marine natural product (+)-spongistatin 1 is, by all accounts, a highly prom- ane-coupling strategy that uses epoxides as electrophiles, Smith noted. This techising 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 ofwet sponge to isolate just 35 mg of the natural product. Without a more plentiful supply (+)-spongistatin 1 is unlikely to nique enables the rapid, stereoselective make it beyond early preclinical testing. construction of orthogonally functionalized 1,5-diols, a feature shared by many adSmith reported that his lab now has in vanced intermediates on the way to (+)hand a synthetic route that he estimates spongistatin 1. Another speaker, chemistry can be used to make gram-scale quantities professor Steven V Ley of Cambridge Uniof the precious natural product. Such an versity, cited a similar dithiane-coupling achievement would open the door to furstrategy as crucial to his own synthesis of ther preclinical and biological testing of (+)-spongistatin 1. this compound. Smith argued that recent scaled-up synThe Smith lab's quest was inspired by theses of (+)-discodermolide and now, (+)the lab's prior successful completion of a spongistatin 1, make it clear that lengthy togram-scale synthesis of another sponge tal syntheses of such complex natural natural product, (+)-discodermolide. The products are no longer limited to delivermaterial provided by its synthesis furthered ing milligrams of product. • the biological and preclinical evaluation of
Spongistatin Synthesis Scaled Up
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