science/technology Everninomicin is a mostly linear structure consisting of eight different sugar groups (dubbed A through H), and it has aromatic esters (Ax and A2) at each end. It has 13 rings in all and includes 35 stereogenic centers. The compound also possesses two sensitive orthoester groups, and these presented the greatest challenge to Nicolaou and coworkers in their synthetic efforts. The orthoester synthetic he total synthesis of the antibiotic nior vice president of chemical research sequence developed by the Scripps everninomicin—one of the most Ashit K. Ganguly (currently research team starts with a 1,2-phenylseleno micomplex oligosaccharides ever professor of chemistry at Stevens Insti- gration step. This activates a carbohymade by organic synthesis—has been tute of Technology, Hoboken, N.J.) and drate unit via formation of a 2-phenylseachieved by chemistry professor K. C. coworkers at Schering-Plough Re- leno glycosyl fluoride intermediate. The intermediate then undergoes Nicolaou and coworkers at Scripps Re- search Institute, Kenilworth, NJ. search Institute, La Jolla, Calif. [Angew. Everninomicin has demonstrated stereocontrolled glycosidation with a Chem. Int. Ed., 3 8 , 3334, 3340, and 3345 promising efficacy against infections of glycosyl acceptor to elongate the sugar chain. The glycosidation pro(1999)]. duces a 2-phenylseleno glycoThe growing prevalence of side, which can be either rebacteria with strong resisductively converted to a 2-detance to antibiotics has posed oxyglycoside or oxidatively a major challenge to the pharconverted to an orthoester. maceutical industry in recent The final oxidative oryears. Everninomicin's claim thoester conversion step—the to fame is that it's a potentially option actually used in the toimportant drug for treating intal synthesis—was developed fections caused by bacteria in the 1980s by chemistry prothat have developed resisfessor Pierre Sinay of Ecole tance to available antibiotics, Normale Supérieure, Paris. including methicillin and vanNicolaou says his group has comycin. Those two drugs another paper submitted now were for a time considered anthat explores the scope of the tibiotics of last resort for treatoverall orthoester methodoloment of multi-drug-resistant Everninomicin builders on Nlcolaou's team include (from left) bacterial infections, but bacte- postdocs Hideo Suzuki, Rosa Maria Rodriguez, and Konstantlna gy, including its use for solidphase synthesis in addition to rial strains resistant to them C. Fylaktakidou and graduate student Helen J. Mitchell. the solution-phase method have been emerging. The everninomicins are bacterial nat- methicillin-resistant staphylococci and used in the everninomicin study. Another challenging feature of the ural products. Two forms of everninomi- vancomycin-resistant streptococci and cin were first isolated from an African enterococci. Schering-Plough currently synthesis was assembly of a Ι,Γ-disacsoil sample in the 1960s but were has the drug in Phase III clinical trials. charide unit linking rings F and G. This shelved because of toxicity problems. The total synthesis devised by Nico- was constructed in a stereocontrolled Everninomicin 13,384-1 (trade named laou is not practical for commercial pro- manner using a tin acetal-containing in Ziracin), the compound Nicolaou and duction of the drug, which is currently termediate, based on a method devel coworkers have now created syntheti- made on a large scale by fermentation. oped earlier in Nicolaou's lab \J. Am. cally, was isolated in the 1980s and However, the synthesis is potentially Chem. Soi, 119,9057 (1997)]. The Nicolaou group's synthetic strat found to be a better drug candidate. Its useful for making analogs of everniegy was "convergent" in that two large structure was determined by former se- nomicin by semisynthesis.
Complex Oligosaccharide Made By Total Synthesis Everninomicin appears active even against drug-resistant bacteria
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NOVEMBER 22,1999 C&EN 6 7
science
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fragments of the molecule were preassembled and then combined. The re searchers' use of their orthoester forma tion sequence to create an orthoester link between rings G and H was a key step in the assembly of a fragment containing rings D, E, F, G, H, and A2. This fragment was coupled to another that included rings Αχ, Β, A, and C. The orthoester for mation sequence was then used a second time—in this case to create the more sen sitive orthoester linkage between rings C and D. Nicolaou and coworkers elaborat ed and deprotected the structure to form thefinalproduct Asked to comment on the synthesis, chemistry professor Stephen Hanessian of the University of Montreal—whose research interests include natural prod uct synthesis and carbohydrate chemis try—says, "It isn't necessarily the diffi culty in synthesizing the individual sug ar units as much as the logistics of functional compatibility that merits ku dos in the assembly of everninomicin." Overall in the synthesis, "a great deal of knowledge regarding selectivity in ma nipulating protective groups was gath ered and considerable light was shed on conformational effects on selective functionalization of carbohydrate templates," Nicolaou and coworkers note. With the synthesis in hand, the stage is now set, they add, for the semisynthesis and bio logical testing of novel everninomicin an alogs as a potential route to the discovery of ever better antibiotics. Stu Borman
After 20 years, focus of lab managers' association is unchanged In 1980, a group of laboratory managers got together to mull over some of the problems associated with running analyt ical laboratories. The chemists shared ex periences with one another, bounced ideas for solutions off their fellow lab managers, and formed an organization to promote networking. Late last month, that organization, the Analytical Labora tory Managers Association (ALMA), cel ebrated its 20th anniversary. Originally made up of lab managers exclusively from university settings, the young association quickly attracted inter estfromthe heads of laboratories in oth er sectors. Managers of industrial, com mercial, and government laboratories, in
