In this project funded by the Chemical Synthesis Program of the Chemistry Division, Professor Richard Fitch of the Department of Chemistry and Physics at Indiana State University will develop a convergent enantioselective method for the synthesis of phantasmidine, a novel alkaloid and a potential nicotinic receptor agonist from the Ecuadoran poison frog Epipedobates anthonyi. Phantasmidine possesses a unique condensed tetracyclic structure incorporating pyridine, furan, pyrrolidine, and cyclobutane rings. An improved synthesis of cyclobutene, its epoxide and the corresponding cis- and trans-2-aminocyclobutanols will be developed, whose stereochemistry will control installation of the remaining stereocenter. A transannular ring closure involving rhodium-catalyzed carbene C-H insertion will be used to close the tetracycle.

This work should produce a sufficient amount of material for a full biological evaluation of phantasmidine and provide initial structure-selectivity relationships among nicotinic receptors to aid the development of selective biological probes. The synthetic methodology that will be developed should be applicable to other related heterocycles as well as the synthesis of cyclobutane-based polymers and other structured materials. These methods and materials can impact several chemical industries, including pharmaceuticals, fine chemicals and polymers. The broader impacts involve the training of undergraduate students and a postdoctoral fellow at a predominantly undergraduate institution. The undergraduate students will participate in the Summer Undergraduate Research Experiences (SURE) program at Indiana State University, aimed at fostering a research culture among students including groups underrepresented in the sciences.

Project Report

Overview: The purpose of this project is to develop a synthetic route to the poison frog alkaloid phantasmidine, a potent nicotinic acetylcholine receptor agonist with potential as a biological probe and therapeutic. Nicotinic receptors are prototypical ligand-gated ion channels and understanding their structure and function, particularly their interaction with neurotransmitters is key to understanding their role in normal physiology and disease. Phantasmidine is a rigid agonist (activator) and its structure represents a useful scaffold for exploring the steric and electronic requirements for the interaction of molecules which activate nicotinic receptors and by analogy other neurotransmitter receptors. Research Plan: Our project was designed around an efficient convergent synthetic sequence arrived at by retrosynthetic analysis of the target molecule (Figure 1). Cutting the molecule approximately in half gives two key intermediates; trans-2-aminocyclobutanol and a 2,6-dihalohomonicotinic acid. The first would be available from 1,3-butadiene, a cheap commercial feedstock for making plastics and the second from a 2,6-dihalopyridine (dichloro and chlorofluoro), both of which are available commercially. Once in hand, these would be brought together through formation of an amide, cyclization through an alkoxide intermediate and formation of a carbon-carbon bond across a ring to complete the tetracycle. Outcomes: We successfully prepared the key synthons, aminocyclobutanol (as both mirror images) and the dihalohomonicotinic acids and their corresponding esters (Figure 2). In doing so, we were able to scale up a photochemical preparation of cyclobutene to a 50-gram scale and optimize its epoxidation to give synthetically practical routes to both of these useful synthetic intermediates. We also developed a mild catalytic reaction to prepare the amide from the amine and ester above as well as prepare a variety of analogs thereof. Though funding has ended, we are continuing work on these molecules and are currently working on the two final ring closures. The preparatory work we have done under this grant and the reagents and equipment it made available have allowed us to continue work even after the end of the funding period. One student funded under this grant is continuing during this academic year and into the coming summer along with another student (using departmental funds). Broader Impacts: This project has involved eleven undergraduate students over four years, including six female, one minority and one international student. These students learned advanced techniques and concepts in organic chemistry and participated in our Summer Undergraduate Research Experiences (SURE) program. In this program, they attended and presented their work at weekly group meetings where they interacted with a cohort of 30-50 other undergraduates in chemistry, physics, biology, geology, and mathematics. All but one of the students in this project have presented their work at national American Chemical Society meetings. The experience and skills obtained through this work have prepared them for the workforce and for graduate/professional schools. Of the eight students who have graduated, one has gone on to medical school, five are working in industry (three as chemists at pharmaceutical companies and two as technicians at analytical laboratories), one is pursuing graduate school in chemistry and the last is pursuing a physical therapy degree.

Agency
National Science Foundation (NSF)
Institute
Division of Chemistry (CHE)
Type
Standard Grant (Standard)
Application #
1012629
Program Officer
Tingyu Li
Project Start
Project End
Budget Start
2010-09-15
Budget End
2014-08-31
Support Year
Fiscal Year
2010
Total Cost
$224,935
Indirect Cost
Name
Indiana State University
Department
Type
DUNS #
City
Terre Haute
State
IN
Country
United States
Zip Code
47809