Michael addition of heterocyclic bases to acceptor molecules is a versatile new method for nucleoside synthesis. Experimental simplicity, efficiency and potential for asymmetric synthesis distinguish it from conventional routes. The proposed research will explore and refine the sequence, and apply it to the preparation of candidate antiviral nucleoside analogues. Equilibrium constants of model systems will be determined (NMR) to define optimal reaction conditions. Asymmetric inductions affording nucleosides with the R configuration at C1' will be attempted with chiral catalysts. The scope of the method will be explored with selective acceptors, and a homologous series of C1'- branched acyclic nucleosides will be prepared and tested to clarify antiherpetic structure-activity relationships. Unsaturated nucleosides of a new type (vinyl) will be obtained, as well as acyclic and carbocyclic derivatives of neplanocin A. A 2'- deoxyguanosine analogue (26), structurally closer to the natural substrate than either acylovir or DHPG, will be synthesized and evaluated for antiviral activity. Student researchers will be exposed to a wide range of modern experimental techniques and concepts. Participants will be involved in significant frontline research in medicinal chemistry. The experience should serve to stimulate students to pursue graduate study and careers in biomedical science.
