This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chiral amino derivatives are important organic compounds, which have been used as building blocks for the synthesis of a variety of pharmaceutical compounds and as auxiliaries and.catalysts in many enan!ioselective organic preparations. Many synthetic drugs, in particular, antibiotics, aministamines, alpha- and beta- adrenoreceptors agonists and antagonist, contain chiral carbons centers with amino groups. In our laboratory we are developing novel methods for the synthesis of amino derivatives that can be applied for the preparation of biologically active molecules. The main goal of this project is to develop novel organic synthetic methodology for the preparation of potential nicotinic acetyl choline receptor (nACHRs) agonist that will be valuable for the treatment of neuron-degenerative diseases, such Alzheimer and Parkinson. The acquired knowledge and expertise through our previous studies on the synthesis and reduction of aromatic N-substituted silyl-, silyloxy-, boryl- and boryloxy imino derivatives with boron reagents will be directed toward the synthesis of nicotine analogues.
Our aim i s to design novel chiral organoborane reagents and synthetic systems that can accomplish high enantioselectivities or diastereoselectivities in the proposed organic transformations. Based on our previous knowledge on the synthesis of arylalkyl amines and organoborane chemistry, we plan to investigated the development and reactivity of new chiral B-substituted-l,3,2-oxazaborolidines and 1,3,2-dioxaborinane-H systems for the synthesis of pyridylalky methanamino ligands. The mechanistic aspects of these processes including the structural factors affecting the reactivity and stereochemical outcome will be addressed. In addition, we will continue to study a Beckman type of rearrangement reaction of discovered in our laboratory, in which aromatic silylated oximes are converted to aniline derivatives. This reaction will be investigated for the synthesis of aromatic heterocyclic amines and amino substituted pyridines, which are active ligands for nicotinic receptors. The proposed methodology will not only contribute significantly, to the development of new organic reaction via borane reagents, but will also explore new routes for the preparation of novel amino pyridine derivatives that will be studied as potential nicotinic receptors ligands. To accomplish our previous stated goals, we have established the following specific objectives: 1. To prepare new organo-borohydride reagents and fully characterize them by B, C and H NMR spectra and X-ray analysis. 2. To investigate the reduction of prochiral model N-substituted-imines with borane and the previously prepared organoboranes reagents, and study the structural factor that affect the stereo-selectivity. 3. To study of use of B-substituted-l,3,2-oxazaborolidines for the C-C bond formation and subsequent transformation of the boronic acid derivatives to amino derivatives. 4. To establish protocols for the synthesis of new amino pyridine and racemic and enantio-enrich arylpyridylmetanamines as nicotinic receptor agonist: 5. To study the borane reduction of pyridyl substituted imines for the synthesis of alkyl and heterocyclic aminopyridines. 6. To test these new amino pyridine and racemic and enantio-enrich arylpyridylmetanamines as potential agonists for neuronal nicotinic receptors (nAChRs) using voltage clamp techniques and recombinant expression of nAChRs in oocytes. 7. To study the optimal stereochemistry of chiral reagents and transition states for the proposed enantioselective reactions using molecular modeling method. Molecular modeling will also be used to establish the correlation between agonist's structure and observed and calculated affinities for the nACH Receptor.
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