Many of today's drugs contain saturated nitrogen heterocyclic rings, thus, it is important to develop new ways to synthesize and modify nitrogen heterocycles. Likewise, it has become important to produce chiral drugs in enantiomerically pure form. For decades, the only stereoselective reactions known to organic chemists were additions of a fourth ligand to heterotopic faces of a trigonal atom. This category includes almost all stereoselective reactions in organic synthesis, and we have accumulated significant insight into the electonic, steric, and dynamic factors that influence these processes. In the past 10 years, significant advances in applying electrophilic substitutions of chiral organometallics (especially organolithiums) as new methods for asymmetric synthesis have been made. This reactivity mode is different from most other asymmetric syntheses in that it involves substitution of a metal attached to a stereogenic carbon atom. Substitution of the metal for an electrophile completes the enantioselective synthesis. Mechanistic understanding of developing methodology is necessary to advancing the field. When contemplating electrophilic substitutions of stereogenic carbanions, one must consider configurational stability, steric course, and aggregation state. If the electrophile is prochiral, two new stereocenters are formed and the question of diastereoselectivity arises. Answering these questions is not always possible; but without answers, mechanistic interpretation is speculative, at best.
The specific aims of this project are: 1. To continue our investigation into the scope and limitations of alpha-aminoorganolithium electrophilic substitutions and sigmatropic rearrangements, with emphasis on stereoselectivity in compounds with multiple stereocenters. Explore further extensions of the methodology such as ring-closing metathesis. 2. To develop improved methods of preparation of chiral organometallics. 3. To further explore the solution and solid state structure of chiral organometallics. Evaluate the effects of ligating atoms and metal effects on configurational and structural dynamics of chiral carbanions. 4. To pursue our recent findings relating to possible stereoelectronic effects on transmetalation and the nature of heteroatom participation in tin-lithium exchanges using rapid injection NMR.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056271-05
Application #
6525403
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1998-05-01
Project End
2002-12-31
Budget Start
2002-09-01
Budget End
2002-12-31
Support Year
5
Fiscal Year
2002
Total Cost
$25,269
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