Polyketides represent a class of small molecules that has had an enormous impact on the human condition. Several natural products and derivatives of this class possess a wealth of pharmacological properties from anti-cancer to antibiotic and even anti-cholesterol activity. Standard methods to prepare these molecules include fermentation and total synthesis. This proposal outlines a new method for the general synthesis of polyketides that is inspired by polyketide synthase, the enzymatic machinery that is utilized in Nature to prepare molecules of this class. This method would capitalize on the use of a solid-supported template to elongate a growing polyketide chain via decarboxylative Claisen reactions between thioesters. If successful, this method could lay the groundwork for an iterative, standardized method for the synthesis polyketides, opening avenues for automated synthesis of natural products and derivatives thereof. PUBLIC HEALTH RELEVANCE: Polyketides such as the tetracyclines, the erythromycins, and the epothilones possess a wealth of pharmacological properties including anti-cancer, antibiotic and anti-cholesterol activity. This proposal outlines a new method for the general synthesis of polyketides that is designed to lay the groundwork for a standardized way to access these molecules to further advance their medicinal potential.