(Principal Investigator's) Many, if not most, of the pharmaceutical agents in use today (worldwide) are nitrogen heterocycles. It i unlikely that this situation will change drastically in the next decade, so continuing investigation of new chemistry in such species is warranted, insofa as it provides new methods of synthesis, understanding of chemical reactivities, and novel compounds. The studies outlined in this proposal seek to fully develop recent fundamental discoveries about the chemistry and synthetic utility of lithiated nitrogen heterocycles. The knowledge gained in these studies is expected to enhance our ability to synthesize complex molecules containing nitrogen heterocycles in an efficient manner. One authority has recently asserted that """"""""Reactions with organolithium species as reagents, reactants, or intermediates are so well established that organolithiums are the most widely used organometallics in contemporary organi chemistry"""""""" (Beak et al, Acc. Chem. Res. 1996, 29, 552-560). The proposed mechanistic studies will provide basic and fundamental knowledge about a class of organolithiums that are of growing importance to organic synthesis, and tha will have an impact beyond the immediate questions posed herein.
The specific aims of this proposal are to: (1) Continue investigation of the scope and limitations of alpha-aminoorganolithium alkylations and sigmatropic rearrangements, with emphasis on stereoselectivity. Develop improved methods o preparation. (2) Apply the sigmatropic rearrangement of N-allyl-2-lithio heterocycles to the synthesis of aza sugars and potential glycosidase inhibitors. (3) Using spectroscopic and cryoscopic techniques, characterize th solution structure of unstabilized alpha-aminoorganolithium species. Attempt t grow crystals for X-ray diffraction analysis. (4) Test the hypothesis that the reason for occasional nonselective reaction of alpha-aminoorganolithiums is du to the intervention of single electron transfer processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056271-02
Application #
2910359
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1998-05-01
Project End
2001-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Miami Coral Gables
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Gawley, Robert E (2010) Overview of Carbanion Dynamics and Electrophilic Substitutions in Chiral Organolithium Compounds. Top Stereochem 26:93-133
Gawley, Robert E; Moon, Kwangyul (2007) Stereoselective [2,3]-sigmatropic rearrangements of unstabilized nitrogen ylides. Org Lett 9:3093-6
Klein, Rosalyn; Gawley, Robert E (2007) Configurational and conformational effects on tin-lithium exchange in alpha-aminoorganostannanes by rapid-injection NMR. J Am Chem Soc 129:4126-7
Gawley, Robert E (2006) Do the terms ""% ee"" and ""% de"" make sense as expressions of stereoisomer composition or stereoselectivity? J Org Chem 71:2411-6
Madan, Sachin; Milano, Peter; Eddings, Daniel B et al. (2005) Conversion of five-, six-, and seven-membered lactams to racemic or scalemic 2-substituted heterocycles by amidoalkylation. J Org Chem 70:3066-71
Gawley, Robert E; Dukh, Mykhaylo; Cardona, Claudia M et al. (2005) Heptapeptide mimic of ohmefentanyl binding in the discontinuous mu-opiod receptor. Org Lett 7:2953-6
Santiago, Marcelina; Low, Eddy; Chambournier, Gilles et al. (2003) Modeling and experiment reveal an unexpected stereoelectronic effect on conformation and scalar couplings of alpha-aminoorganostannanes, with possible relevance to the tin-lithium exchange reaction. J Org Chem 68:8480-4
Iula, D M; Gawley, R E (2000) Synthesis and reactivity of dipole-stabilized but unchelated alpha-aminoorganolithiums. J Org Chem 65:6196-201
Chambournier, G; Gawley, R E (2000) Synthesis and reactivity of conformationally locked alpha-aminoorganostannanes and alpha-aminoorganolithiums. Discovery of a surprising configurational requirement for transmetalation. Org Lett 2:1561-4
Gawley, R E; Low, E; Chambournier, G (1999) Unusual conformational effect in alpha-aminoorganostannanes. Org Lett 1:653-5