METHODS FOR THE SITE-SELECTIVE INTRODUCTION OF HALOGEN INTO NATURAL PRODUCTS

摘要

Organohalides (e.g., organofluorides) represent a rapidly expanding proportion of molecules used in pharmaceuticals, diagnostics, agrochemicals, and materials. The present invention exploits the naturally occurring acetate condensation pathway as a means of introducing halogenated building blocks into natural product scaffolds. In an exemplary embodiment, the invention provides a pathway involving at least one polyketide synthase system and utilizes haloacetate or a haloacetate synthon (e.g., halomalonate) to incorporate an organohalide into the polyketide backbone in vitro. In an exemplary embodiment, the invention provides an analogous method for site-selective introduction of haloacetate or a synthon into polyketide products in vivo. The present invention expands the scope of existing chemical methods for producing halogenated natural product scaffolds such as complex halogenated natural products.

主权项

1. An enzymatically mediated method for producing a halogenated ketide, said method comprising:
(a) a first condensation reaction comprising contacting a polyketide synthase and a substrate for the polyketide synthase with a compound according to Formula I:  in which X is a member selected from F, Cl, Br and I,wherein said polyketide is competent to catalyze the condensation and the contacting is under conditions appropriate for the condensation.