The objective of this research program is to discover and develop new reaction methods en route to the synthesis of complex bioactive molecules. Research in our group at Caltech is focused on the general area of chemical synthesis. Specifically, our science has been devoted to the development of new strategies for the preparation of complex molecules that possess significant structural, biological, and physical properties. Concurrent with this program of target-driven synthesis is a dedicated effort directed toward the development of new reaction methods that we anticipate will be useful for a range of applications across numerous disciplines, including synthetic and organometallic chemistry, chemical biology, and human medicine. In this proposal, we outline a multifaceted and integrated program in organic synthesis that encompasses the total synthesis of the highly biologically active natural product jorumycin. Jorumycin, isolated from the sea slug Jorunna funebris, has been shown to possess exceedingly potent antitumor and antibiotic activity (Gram-positive and Gram- negative). The proposed research will provide access to jorumycin and previously unavailable analogs to be used in further biological evaluation. We illustrate a rapid and unusual approach to the construction a pentacyclic core, common to the members of the bis-tetrahydroisoquinoline class of natural product. Upon completion of our target and a host of designed analogs, we will collaborate with Dr. Dennis Slamon of the Translational Oncology Research Laboratory at UCLA who will undertake biological evaluation of our materials. Studies performed at UCLA in conjunction with DMPK studies at WuXi AppTec will then indicate how we can improve upon the architectures already developed by nature to produce efficacious small organic molecules for use as potential chemotherapeutic agents.
to Public Health: At the core of chemistry rests the power to manipulate the elements for the preparation of specific arrays of atoms in a predictable and reliable fashion. As synthetic chemists, our capacity to construct molecules with exquisite precision is unique in the sciences. In this proposal we outline a novel approach toward constructing an important molecular framework by implementing a crosscutting method that enables the ready preparation of potentially important molecules for human medicine.
