Combinatorial chemistry, initially employed to prepare peptide and oligonucleotide libraries, has provided a new paradigm for the chemical synthesis, most examples of combinatorial synthesis of small molecules have been based on linear divergent strategies for accessing chemical diversity. However,, target oriented syntheses of complex natural products have generally been performed using convergent synthesis approaches. In this project, we will outline syntheses of natural product-like libraries of """"""""expanded diversity"""""""" using convergent, diversity-oriented synthesis. The approach is based on construction of chemically diverse, hybrid structures by convergent """"""""mixing and matching"""""""" of complex sub-library """"""""fragments"""""""" produced by solution-phase or solid-phase synthesis. We have termed this general approach """"""""Domain Shuffling"""""""" which is inspired by consideration of biologically active dimeric structures and examination of molecules with discrete """"""""chemical domains."""""""" The Project is organized into three general secretions and utilizes sib-libraries prepared in projects 1 and 2 of this proposal to create hybrid molecules: 1) Convergent, Diversity-Oriented Synthesis of Polypropionate-Derived Libraries 2) Convergent, Diversity-Oriented Synthesis of """"""""Pseudo-Dimeric"""""""" Molecules: and 3) Implementation of Domain Shuffling as a New Paradigm for Diversity Oriented Synthesis. It is anticipated that the convergent, diversity-oriented synthesis described herein will greatly enhance the molecular complexity and chemical diversity of target molecules and produce numerous biologically active molecules for biological evaluation.
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