Studies on the Total Synthesis and Structure Determination of RP 66453

Download or read book Studies on the Total Synthesis and Structure Determination of RP 66453 written by Paul John Krenitsky and published by . This book was released on 2003 with total page 266 pages. Available in PDF, EPUB and Kindle. Book excerpt: Neurotensin (NT) is a linear tridecapeptide first isolated from bovine hypothalamus shown to have pharmacological properties similar to dopamine antagonists, and as such, analogs of NT may be useful in the treatment of schizophrenia, psychoses, or depression. In the course of a screening program to identify compounds that displace NT from its receptor, RP 66453 was isolated and partially characterized. The connectivity structure was determined through spectroscopic methods and published in 1998, however the relative and absolute stereochemistry remain unsolved. RP 66453 was found to possess a unique and highly strained bicyclic ring system consisting of a 15-membered (AB) ring containing an endo aryl-aryl bond and a 14-membered (BC) ring containing a diaryl ether. This highly strained bicyclic tetrapeptide has never before been prepared synthetically. The S,S -isomer of a fully functionalized BC ring system of RP 66453, which constitutes an unusual reversed 14-membered cycloisodityrosine, was assembled through use of a key diaryl ether macrocyclization reaction enlisting a phenoxide nucleophilic aromatic substitution reaction of an o -fluoro nitroaromatic. The desired stereochemistry was maintained during the course of this synthesis, so it was expected that the conditions used for the cyclization reaction and removal of the nitro group would be suitable to apply to the synthesis of RP 66453. An appropriately functionalized derivative of the (S,S,S )-diastereomer of the 15-membered AB ring system of RP 66453 has been prepared by an unusually effective Suzuki coupling to form the aryl-aryl bond followed by macrolactamization. An optimal site of macrolactamization was identified, and the conformational and atropisomers issues associated with this unusual ring system were established. Two different routes were developed for the synthesis of the unique and highly strained bicyclic ring system of RP 66453. The first route employed diaryl ether formation for the final ring closure reaction, and the second route accomplished the final ring closure through macrolactamization. While not establishing the stereochemistry of RP 66453, these syntheses confirmed the structure of the carbon skeleton of the natural product and confirmed that the natural product does not possess the P,S,S,S,S -configuration.