Dr. Miller's research group has received considerable worldwide recognition for the development of new methods for the asymmetric syntheses of functionalized beta-lactams, the core unit of the most important class of antibiotics used throughout the world. Early results led to the development of an efficient, and generally applicable, synthetic approach based on a biomimetic N-C4 closure (5 to 6). This process and subsequent chemistry, especially on novel N-hydroxy beta-lactams (7) introduced by the Miller group has facilitated the synthesis of several interesting heterocyclic compounds, including new antibiotics (Scheme 1). The chemical versatility of the methods indicates that a variety of new beta-lactams may be synthesized for studying important structure-activity relationships. Essentially any beta-lactam can now be prepared from any beta-hydroxy carboxylic acid and many applications of this methodology have been utilized in both academic and industrial labs.
Extensions to final monocyclic and bicyclic beta-lactams for biological studies required development of new methodology for the preparation of optically pure precursor beta-hydroxy acids and eventually for elaboration to final targets. Thus, a number of new chemical and enzyme-mediated processes have been devised by the Miller group. Recently they discovered a whole new mechanistically novel and synthetically versatile reaction type (7 to 8) based on the N-hydroxy beta-lactams. For instance, synthetic N-tosyloxy beta- lactams have been found to undergo nucleophilic attack at the a-carbon (C-3), a position which typically is nucleophilic itself, with concommitant N-O reduction to give a,beta- disubstituted beta-lactams with complete control of relative and absolute stereochemistry.
Since the novel structural aspects of these N-hydroxy beta-lactams impart unusual chemical reactivity to the beta-lactam by making every atom of the core ring system electrophilic, derivatives of N-hydroxy beta-lactams also were tested for biological activity. Early on they found that appropriately substituted forms of these simple heteroatom activated (N- hydroxy) beta-lactams, including the oxamazins (9) and monosulfactams (10), had potent antibiotic activity. These results led to extensive reconsideration of structure-activity relationships of beta-lactam antibiotics by scientists around the world. More recently, Miller's group demonstrated that simple N-tosyloxy beta-lactams, such as 4-phenyl-N-tosyloxy 2-azetidinone (20), are very potent totally novel class of beta-lactamase inhibitors. beta-Lactamases are enzymes evolved by microbes to intercept and destroy currently used beta-lactam antibiotics, thus rendering the microbe resistant to the major weapons in our current arsenal of antimicrobial agents.
