This research program seeks to provide the medicinal chemistry and drug discovery communities with practical and effective methods for the rapid and enantiocontrolled construction of diverse, biologically relevant molecular motifs from conceptually simple, yet synthetically powerful """"""""enantiomeric scaffolds"""""""". The easy production in quantity of single enantiomers of inexpensive, air-stable metal pi-complexes of unsaturated heterocyclic organic ligands provides """"""""organometallic chirons"""""""" whose flexible and novel synthetic elaboration can generate, after demetalation, a highly varied range of biologically significant molecular structures in an enantiospecific fashion. This research, both in progress achieved to date and in the future research design and methods demonstrates that enantiomeric scaffolding using organometallic chirons is a valuable and versatile strategy for enantiocontrolled synthesis and for the exploration of chemical space. The development of new small molecule drugs for the treatment of disease, for the amelioration of debilitating medical conditions, and for improving the general state of health of the public relies to a significant extent on the synthetic power of chemistry. This research describes a general strategy to carry out the highly controlled synthesis of structurally divergent families molecules with demonstrated medical and biological applications. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM043107-16
Application #
7392356
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Schwab, John M
Project Start
1989-12-01
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
16
Fiscal Year
2008
Total Cost
$306,000
Indirect Cost
Name
Emory University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Wong, Heilam; Garnier-Amblard, Ethel C; Liebeskind, Lanny S (2011) Organometallic enantiomeric scaffolding: a strategy for the enantiocontrolled construction of regio- and stereodivergent trisubstituted piperidines from a common precursor. J Am Chem Soc 133:7517-27
Coombs, Thomas C; Huang, Wenwei; Garnier-Amblard, Ethel C et al. (2010) Novel Substitutions of 1-Alkoxy- and 1-Arylsulfonyloxy-?-Allylmolybdenum Complexes. A Case for ?-Alkenyl Carbene Complexes as Intermediates. Organometallics 29:5083-5097
Cheng, Bo; Liebeskind, Lanny S (2009) Organometallic enantiomeric scaffolding. A molybdenum-mediated intramolecular nucleophilic ketalization-demetalation cascade. Total synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin. Org Lett 11:3682-5
Coombs, Thomas C; Zhang, Yongqiang; Garnier-Amblard, Ethel C et al. (2009) Organometallic enantiomeric scaffolding. Sequential semipinacol/1,5-""Michael-like"" reactions as a strategic approach to bridgehead-quaternary center aza[3.3.1]bicyclics: application to the total synthesis of (-)-adaline. J Am Chem Soc 131:876-7
Chen, Wenyong; Liebeskind, Lanny S (2009) A new reaction motif: ""homo-S(N)2'-like"" direct nucleophilic addition to neutral eta(3)-allylmolybdenum complexes. total synthesis of the antimalarial (+)-isofebrifugine. J Am Chem Soc 131:12546-7
Garnier, Ethel C; Liebeskind, Lanny S (2008) Organometallic enantiomeric scaffolding: general access to 2-substituted oxa- and azabicyclo[3.2.1]octenes via a Bronsted acid catalyzed [5 + 2] cycloaddition reaction. J Am Chem Soc 130:7449-58
Coombs, Thomas C; Lee 4th, Maurice D; Wong, Heilam et al. (2008) Practical, scalable, high-throughput approaches to eta3-pyranyl and eta3-pyridinyl organometallic enantiomeric scaffolds using the Achmatowicz reaction. J Org Chem 73:882-8
Arrayas, Ramon Gomez; Yin, Jingjun; Liebeskind, Lanny S (2007) The enantiomeric scaffold approach to highly functionalized 1-oxadecalines: enantio- and regiocontrolled [4 + 2] cycloadditions of 5-alkenyl-eta3-pyranylmolybdenum complexes. J Am Chem Soc 129:1816-25
Arrayas, Ramon Gomez; Liebeskind, Lanny S (2003) Eta3-pyranyl and eta3-pyridinyl molybdenum pi-complexes as chiral scaffolds for the enantioselective construction of substituted oxa- and aza[3.3.1]bicyclics: first enantio- and regiocontrolled [5+3] cycloaddition reactions. J Am Chem Soc 125:9026-7
Shu, Chutian; Liebeskind, Lanny S (2003) Enantiocontrolled synthesis of 2,6-disubstituted piperidines by desymmetrization of meso-eta-(3,4,5)-dihydropyridinylmolybdenum complexes. application to the total synthesis of (-)-dihydropinidine and (-)-andrachcinidine. J Am Chem Soc 125:2878-9

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