Synthetic Organic Methodology Development in Organophosphorus and Organonitrogen Chemistries
Associate Professor, retired
Fax: (406) 994-5407
cmcclure chemistry.montana.edu
B.A., Northwestern University, 1975; M.S., University of Wisconsin-Madison, 1977; Ph.D., University of Wisconsin-Madison, 1985; Postdoctoral, Cambridge University, England, 1985-87
Courses:
· CHMY 523 ORGANIC REACTION MECHANISMS
Awards:
American Cyanamid Academic Awardee, 1990; Procter and Gamble University Exploratory Research Program Awardee, 1991-94; National Science Foundation Career Advancement Award Recipient, 1994-96; Cox Family Award for Creative Scholarship and Teaching, Montana State University, 1999
McClure Group Overview
Organic Chemistry: Development of new methods in synthetic organic chemistry. Synthesis of biologically active natural products and analogues. Organophosphorus chemistry, alkaloid and cyclic peptide synthesis.
Current Research Interests: We are developing new synthetic methods with the goal of applying them to the syntheses of complex, biologically active natural products and their analogues. Our current synthetic goals are phosphonate derivatives of phosphate-containing compounds (nucleotides, sphingosines, carbohydrates, etc.), as well as alkaloids and cyclic peptides. We are pursuing three general strategies to achieve our synthetic goals, as outlined below. To support the synthetic work, we are beginning to analyze the pathways of our reactions by molecular modelling and ab initio calculations.
Keywords:
Organic, Synthesis
Pentacovalent Organophosphorus Compounds in the Synthesis of Substituted Phosphonates
Phosphonate containing compounds are of biological interest as antimetabolites and enzyme active-site probes. They also have medicinal value as antivirals,antibiotics, and calcium regulators. The compounds initially developed are the simple phosphonate analogues of the active phosphate-containing compounds. We are currently developing a mild and versatile method based on pentacovalent oxaphospholenes to produce variously substituted phosphonates. We have discovered that the pentacovalent oxaphospholene, 1, resulting from the reaction of an enone with a trialkyl phosphite, will condense under neutral conditions with a variety of electrophiles to produce highly functionalized phosphonates. We are currently applying this method to produce various phosphonate containing compounds that will be tested for any bio-activity. Our current targets are phosphonate derivatives of inositol and furanose phosphates, sphingomyelins, and nucleoside or nucleotide analogues. We are continuing to screen new enones and P(III) compounds in the formation of new pentacovalent organophosphorus compounds, and their subsequent reactivities towards electrophilic reagents.
Keywords:
Organic, Synthesis
Cyclic Peptides Via Large Ring Conformational Control
Cyclic peptides are a pharmacologically important class of compounds, but problems arise in their syntheses when they contain unusual amino acids with the unnatural D configuration. One strategy for the construction of such cyclic peptides would be the use of macrocyclic conformational control in the establishment of the necessary stereocenters by various addition reactions. We have been utilizing molecular modeling calculations on various macrocyclic presursors of the cyclic peptide to predict which intermediate would give the largest conformational control in the reactions to produce the asymmetric centers, and are currently synthesizing these precursors. This molecular modeling analysis could provide potentially valuable insights into the structures and reactive conformations of the cyclic peptides, leading to further SAR studies and analogue development.
Keywords:
Organic, Synthesis
Transition State and Molecular Orbital Calculations.
We are also currently involved in performing high level (ab initio) calculations on several of our systems to try to explain the reactivities observed or to predict the reactivities. To better understand the electronic requirements of the ODPM photorearrangement, we have implemented ab initio and density functional computational methods using SpartanTM. Our primary goal is to assemble a computational model which will enable us to determine the possible effects that the double bond substituents might have on the HOMO/LUMO bandgap, and their resultant effect on ODPM photoisomerization reactivities.
Keywords:
Organic, Synthesis
Alkaloid Synthesis via the Oxa-di-pi-methane Photochemical Rearrangement
The constant discoveries of new biologically active nitrogen heterocycles, such as pyrrolizidine, indolizidine and tropane alkaloids, continue to attract interest in the development of new methodologies for their syntheses. Many of these alkaloids exhibit potent antibiotic and antitumor properties. We are currently exploring the use of an aza-variant of the photochemical oxa-di-pi-methane rearrangement to produce pyrrolizidine, indolizidine and tropane alkaloids. The photochemical oxa-di-pi-methane (ODPM) rearrangement of azabicyclo[2.2.2]-octenones (2, 3) and azabicyclo[3.2.2]nonenones (4, 5) would yield tricyclic products in which the 3-membered ring could be cleaved by nucleophiles or base to produce azabicyclo[3.3.0]octanones (pyrrolizidines), azabicyclo[3.2.1]octanones (tropanes), or azabicyclo [4.3.0]-nonanones (indolizidines). In order to quickly access the photoprecursors, we are also developing methodology based on the Diels-Alder reaction of various dihydropyridine derivatives.
Keywords:
Organic, Synthesis
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