SCIENCE
Penn Chemists Synthesize Complex Natural Antibiotics Synthesis of stereochemically intricate bacterial products efrotomycin and aurodox achieved for doctoral thesis offers new synthetic methods Ron Dagani, C&EN Washington
Organic chemists at the University of Pennsylvania have succeeded in synthesizing two structurally com plex, naturally occurring antibiot ics that may find commercial use as growth promoters in livestock. Their achievement highlights some new synthetic methods that promise to expand chemists' abilities to con struct other intricate natural prod ucts in the laboratory. A scientist familiar with the syn theses tells C&EN that they consti tute "a very remarkable piece of w o r k / ' not only because the target molecules are stereochemical Hy dras, but because the bench work was carried out essentially by one person—graduate student Roland E. Dolle, working with professor K. C. Nicolaou. Their synthetic targets were au rodox and efrotomycin, the two most prominent members of a recently discovered class of antibiotics called elfamycins. Each compound is a product of a different soil bacterium. Aurodox, the simpler of the two, was first isolated by a Hoffmann-La Roche group, which also unraveled its structure. Efrotomycin, which is a disaccharide derivative of aurodox, was isolated and structurally charac terized by a group at Merck Sharp & Dohme. Dolle took on the task of synthe sizing these two molecules as his Ph.D. thesis project. The work, which was supported by funds from
the National Institutes of Health, the Camille and Henry Dreyfus Foundation, and Merck, has been submitted for publication in the Journal of the American Chemical Society. However, details of the work already have been disseminated at several conferences, including the recent ACS meeting in Philadelphia. The total synthesis of efrotomycin posed some formidable stereochemi cal challenges. The molecule has 21 stereocenters plus seven double bonds, each possessing a specific configuration. These 28 stereochemi cal elements thus offer the possibili ty of 2 28 or 268,435,460 different stereoisomers, from which Nicolaou targeted only the one correspond ing to natural efrotomycin. At the outset, a number of key intermediates had to be prepared. One of these was the optically ac tive molecule goldinolactone, a 7-lactone fused to a tetrahydropyran ring. Another crucial intermediate was a tetrahydrofuran fragment con taining four ring substituents, all of them cis to one another.
For both of these, the Pennsylva nia researchers pursued two distinct ly different approaches that Nico laou says are "currently fashionable" among chemists seeking to prepare complex, "chirally r i c h " natural products. In one of these approaches, called acyclic stereoselection, one starts with prochiral molecules and selectively builds stereocenters one by one using open-chain interme diates. For example, to construct goldinolactone via this route, the chemists began with a simple pro chiral ketolactone. The second ap proach, by contrast, involves starting with an optically active carbohy drate. For goldinolactone, the start ing material was L-(—)-mannose, a molecule rich in stereocenters. Nicolaou and Dolle pursued both routes because they were curious as to which would turn out to be the most efficient. Both approaches got good marks, although in terms of overall efficiency, acyclic stereoselection came out ahead in the goldinolactone synthesis, Nicolaou says.
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Dolle (left) and Nicolaou: targeted stereochemical Hydras October 15, 1984 C&EN
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